Quality Control Mechanisms of Mitochondria: Another Important Target for Treatment of Peripheral Neuropathy

Abstract

Mitochondria provide energy for various cellular activities and are involved in the regulating of several physiological and pathological processes. Mitochondria constitute a dynamic network regulated by numerous quality control mechanisms; for example, division is necessary for mitochondria to develop, and fusion dilutes toxins produced by the mitochondria. Mitophagy removes damaged mitochondria. The etiologies of peripheral neuropathy include congenital and acquired diseases, and the pathogenesis varies; however, oxidative stress caused by mitochondrial damage is the accepted pathogenesis of peripheral neuropathy. Regulation and control of mitochondrial quality might point the way toward potential treatments for peripheral neuropathy. This article will review mitochondrial quality control mechanisms, their involvement in peripheral nerve diseases, and their potential therapeutic role.

Introduction

Mitochondria generate the ATP that energizes cellular processes. In addition to oxidative phosphorylation and the tricarboxylic acid cycle, mitochondria regulate calcium homeostasis, membrane potential, production, and quarantine of reactive oxygen species (ROS), cellular metabolism, inheritance of mitochondrial DNA (mtDNA), and apoptosis (van der Bliek et al., 2017). Mitochondria maintain their networks through highly regulated quality control mechanisms (Ma et al., 2020). The concept of quality control of mitochondria includes mitochondrial dynamics and mitophagy (Ni et al., 2015). Dynamics refers to mitochondrial fusion and fission (Chan, 2020).

Peripheral neurons have a high energy demand and require stable mitochondria dynamics to distribute them in axons (Safiulina and Kaasik, 2013). Mitophagy eliminates dysfunctional mitochondria by moving them to lysosomes when mitochondria are affected by mutations in the coding genes or pathogenic factors such as chemotherapeutic agents and diabetes (Youle and Narendra, 2011; Pickles et al., 2018). After mitochondrial injury, increased membrane permeability leads to the release of a large amount of ROS. This oxidative stress is the mechanism of peripheral nerve injury and the cause of pain (Flatters, 2015). Of note, Schwann cells form myelin sheaths around peripheral nerves, and their mitochondria play vital roles in axon development and functional regulation (Ino and Iino, 2017).

For these and other reasons, the dysfunction of mitochondrial quality control is thought to participate in the development of peripheral neuropathy. Researchers have achieved impressive results regarding these mechanisms.

Mechanism of Mitochondrial Quality Control

Mitophagy

Autophagy is a process in which cellular components are encapsulated in a double-layer membrane structure called the autophagosome and are digested by lysosomes (Dikic and Elazar, 2018). Depending on the contents being phagocytized, autophagy can be nonselective or selective (Xu et al., 2021).

Mitophagy, initially proposed by John J. LeMasters, is the selective phagocytosis of damaged mitochondria (Lemasters, 2005), and is mediated by specific proteins (Zaffagnini and Martens, 2016). Mitophagy has been identified in cells under normal physiological conditions (Ding and Yin, 2012). For example, mitophagy eliminates sperm-derived mitochondria, promotes maternal inheritance of mtDNA (Youle and Narendra, 2011; Roberts et al., 2016), and eliminates the mitochondria of developing erythrocytes (Pickles et al., 2018). Peripheral neurons are postmitotic and nonproliferating cells (Roberts et al., 2016); rapid elimination of dysfunctional mitochondria is probably essential for protecting neurons against oxidative damage and degeneration.

Ubiquitin-mediated mitophagy

The classical pathway of ubiquitin-mediated mitophagy is PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy (Amadoro et al., 2014). PINK1 protein is a serine/threonine kinase (Rasool and Trempe, 2018). In a physiological state, it anchors mitochondria through its N-terminal mitochondrial targeting sequence (Durcan and Fon, 2015), and it is imported into the mitochondria through the translocase of outer membrane and translocase of inner membrane complexes (Abe et al., 2000; Lazarou et al., 2012; Ashrafi and Schwarz, 2013; Eiyama and Okamoto, 2015; Liu et al., 2018a; Rasool and Trempe, 2018).

PINK1 cleaved by mitochondrial processing peptidase (MPP) in the mitochondrial matrix and presenilin-associated rhomboid-like protein (PARL) in the inner membrane (Jin et al., 2010; Deas et al., 2011; Meissner et al., 2011; Shi et al., 2011; Greene et al., 2012; Bingol and Sheng, 2016). The fragments are eventually transferred outside the mitochondria and hydrolyzed by the proteasome (Ashrafi and Schwarz, 2013).

Parkin is an E3 ubiquitin ligase in the cytoplasm with a ubiquitin-like domain (UblD) at the N-terminal (Seirafi et al., 2015). UblD inhibits the activity of Parkin under physiological conditions (Trempe et al., 2013; Wauer and Komander, 2013; Nguyen et al., 2016) (Fig. 1A).

FIG. 1.

PINK1-Parkin-mediated mitophagy. (A) Under normal circumstances, PINK1 can be transported from the outer membrane of mitochondria to the inner membrane via TOM and TIM complexes. Then PINK1 is catabolized by MPP and PARL. (B, C) In damaged mitochondria, PINK1 accumulates in the outer membrane and phosphorylates Parkin and poly-UB chains. Activated Parkin generates more poly-UB chains. Adaptor proteins recognize the poly-UB chains and recruit LC3-II to move to damaged mitochondria. Eventually, mitochondria are encased by autophagosomes. MPP, mitochondrial processing peptidase; PARL, presenilin-associated rhomboid-like protein; PINK1, PTEN-induced putative kinase 1; poly-UB, polyubiquitin; TIM, translocase of inner membrane; TOM, translocase of outer membrane. Color images are available online.

When damaged mitochondria lose their membrane potential, PINK1 cleavage is inhibited, leading to PINK1 accumulation on the outer membrane (Narendra et al., 2010; Durcan and Fon, 2015). After PINK1 phosphorylates Ser65 in Parkin's UblD and polyubiquitin (poly-UB) chain, Parkin E3 ubiquitin ligase activity is activated and translocates to the damaged mitochondrial outer membrane (Kim et al., 2008; Narendra et al., 2010; Kondapalli et al., 2012; Koyano et al., 2014; Shiba-Fukushima et al., 2014; Okatsu et al., 2015; Sauvé et al., 2015).

Parkin generates more poly-UB chains (typical mitochondrial ubiquitin chains include lys48 and lys63, whereas atypical ones include lys11 and lys6) on mitochondria, which are subsequently phosphorylated by PINK1 (Kulathu and Komander, 2012; Ordureau et al., 2014, 2015; Lazarou et al., 2015; Seirafi et al., 2015) (Fig. 1B).

Those that recognize the ubiquitin chain and recruit LC3 to move to damaged mitochondria are called adaptor proteins, including ubiquitin-binding protein p62 (sequestosome-1, also known as SQSTM1/p62), optineurin (OPTN), nuclear dot protein 52 (NDP52), TAX1-binding protein 1 (TAX1BP1), and neighbor of BRCA1 gene protein (NBR1) (Geisler et al., 2010; Ma et al., 2020) (Fig. 1C). Eventually, with the help of adaptor proteins, autophagosomes phagocytize mitochondria, and lysosomes further digest autophagosomes. PINK1 also directly recruits adaptor proteins and mediates mitophagy (Lazarou et al., 2015; Yamada et al., 2019).

Receptor-mediated mitophagy

Several proteins on the outer mitochondrial membrane have the LC3-interacting region (LIR) and bind directly to LC3 to induce autophagy, called receptor-induced mitophagy (Hanna et al., 2012; Zhu et al., 2013; Liu et al., 2014; Yamaguchi et al., 2016). Two types of mitophagy receptors have been identified in mammals. NIP-3-like protein X (NIX/BNIP3L) and BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) interact with Bcl-2. The other is FUN14 domain-containing protein 1 (FUNDC1) (Liu et al., 2014; Chen et al., 2016).

The elimination of mitochondria in mature red blood cells requires the mediation of NIX/BNIP3L (Schweers et al., 2007; Sandoval et al., 2008; Zhang and Ney, 2009a; Novak et al., 2010). In hypoxia-mediated mitophagy, both types of mitophagy receptors play a role (Tracy et al., 2007; Zhang and Ney, 2009b; Liu et al., 2012). NIX/BNIP3L and BNIP3 are transcriptionally regulated by hypoxia-inducible factor (HIF) and Forkhead Box O3 (FOXO3) (Sowter et al., 2001; Chinnadurai et al., 2008). FUNDC1-mediated mitophagy activity is regulated by reversible phosphorylation at the post-translational level (Feng et al., 2013).

Specifically, under normal physiological conditions, Tyr18 of FUNDC1 is phosphorylated by Src kinase, and Ser13 is phosphorylated by casein kinase 2 (CK2) (Fig. 2A); under hypoxic stress, Tyr18 and Ser13 are simultaneously dephosphorylated and activate FUNDC1-mediated mitophagy (Chen et al., 2014; Liu et al., 2014) (Fig. 2B, C). A PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is responsible for the dephosphorylation of FUNDC1 Ser13 site, whereas CK2 antagonizes the effect of PGAM5 and inhibits mitophagy (Chen et al., 2014; Yu et al., 2020a). Unc-51 like autophagy activating kinase 1 (ULK1) is recruited to fragmented mitochondria and phosphorylates Ser-17 of FUNDC1 to regulate mitophagy (Wu et al., 2014).

FIG. 2.

FUNDC1-mediated mitochondrial autophagy. (A) In normal conditions, Tyr18 and Ser13 of FUNDC1 are phosphorylated by Src kinase and CK2, respectively. (B, C) In damaged mitochondria, ULK1 phosphorylates Ser17 and PGAM5 dephosphorylates Ser13 on FUNDC1. Dephosphorylation of Try18 promotes the interaction between FUNDC1 and LC3. Eventually, mitochondria are encased by autophagosomes. CK2, casein kinase 2; FUNDC1, FUN14 domain-containing protein 1; PGAM5, PGAM family member 5, mitochondrial serine/threonine protein phosphatase; ULK1, Unc-51-like autophagy activating kinase 1. Color images are available online.

Mitochondrial dynamics

Under the electron microscope or fluorescence microscope, it can be dynamically observed that the mitochondrial probes disperse from one mitochondrion to two, suggesting that mitochondria are a dynamic network enterprise characterized by continuous division and fusion (Wai and Langer, 2016).

Mitochondrial dynamics maintains the morphology, number, cytoplasm, axon distribution, and physiological functions of peripheral nerve mitochondria (Meyer et al., 2017). Mitochondrial dynamics also regulate various mitochondrial functions, including mtDNA stability, apoptosis, and responses to cellular stress and mitophagy (Olichon et al., 2003; Youle and Karbowski, 2005; Twig and Shirihai, 2011; El-Hattab et al., 2018; Tong et al., 2020). In mammals, mitochondrial fusion and fission are indispensable, and even slight defects in mitochondrial dynamics can lead to disease (Chung et al., 2018).

Mitochondria fission

In mammals, an essential protein regulating mitochondrial fission is dynamic-related protein 1 (DRP1) (Mishra and Chan, 2016). Under physiological conditions, DRP1 is located in the cytoplasm (Schmitt et al., 2018). When stimulated by mitochondrial fission factors (MFFs), DRP1 is recruited to the outer membrane of mitochondria to form oligomers under the assistance of receptor proteins (Kalia et al., 2018). The oligomers form a ring structure around the mitochondria and then hydrolyze GTP with its GTPase activity to break the mitochondria apart (Wai and Langer, 2016) (Fig. 3A). The fission produces small and depolarized mitochondria that are eliminated by mitophagy (Poole et al., 2008; Twig et al., 2008; Twig and Shirihai, 2011; El-Hattab et al., 2018).

FIG. 3.

Mitochondria fission and fusion. (A) Mitochondria fission: DRP1 recruits to the outer membrane of mitochondria to form a ring structure around the mitochondria and breaks the mitochondria apart. (B) Mitochondria fusion: Mfn1 and Mfn2 form a homodimer or heterodimer to promote the formation of trans-tethering between the outer membranes. OPA1 fuses the inner membranes. DRP1, dynamic-related protein 1; Mfn1, Mitofusins 1; Mfn2, Mitofusins 2; OPA1, optical atrophy 1 protein. Color images are available online.

The receptor proteins of mitochondria include the MFF and mitochondrial dynamics 49 and 51 (MID49/MID51), whereas the role of fission protein 1 (Fis1) in mitochondrial fission of mammals is controversial (James et al., 2003; Yoon et al., 2003; Stojanovski et al., 2004; Osellame et al., 2016; Kalia et al., 2018; Yu et al., 2020b). Inhibition of DRP1 expression or phosphorylation can reduce neuronal apoptosis and protect neurons (Kim et al., 2016; Whitley et al., 2019).

Mitochondrial fusion

Because mitochondria have double-layer membranes, complete fusion requires the merging of both the outer and inner membranes. Outer membrane fusion is mediated by the mitofusins 1 and 2 (Mfn1/2) (Qi et al., 2016; Chandhok et al., 2018). First, Mfn1 and Mfn2 form a homodimer or heterodimer that promotes the formation of trans-tethering between the two adjacent outer membranes (Griffin and Chan, 2006; Qi et al., 2016). Subsequently, the two proteins exert GTPase activity to hydrolyze GTP and fuse the outer membranes of two mitochondria with conformational changes (Ryan and Stojanovski, 2012; Flippo and Strack, 2017).

Optical atrophy 1 protein (OPA1) is the core of mitochondrial inner membrane fusion, and it is involved in maintaining the shape of mitochondrial cristae (Olichon et al., 2002; Cogliati et al., 2013; Patten et al., 2014). Fusion of the inner membrane is induced when OPA1 is present on any of the trans-tethered mitochondria (Alexander et al., 2000; Cipolat et al., 2004; Meeusen et al., 2004) (Fig. 3B). Although the mechanism by which OPA1 induces inner membrane formation has not been fully established, a study reported that OPA1 needs to be hydrolyzed by a protease to form a short isoform before it can exert its action (Wang et al., 2021).

Molecular mechanisms upstream of mitochondrial quality regulation

The regulation of mitochondrial quality in peripheral nerves is not an isolated molecular mechanism, and it is often combined with other organelles or molecules in the cell to maintain cell homeostasis. The molecular mechanisms upstream of mitochondrial quality regulation include oxidative stress, endoplasmic reticulum stress, unfolded proteins, Ca²⁺, and inflammation. However, mitochondrial quality regulation is the most critical link, which can determine the fate of peripheral nerve cells. Refer Table 1 for related molecular pathways and specific mechanisms.

Table 1.

Upstream Incentives and Mechanisms of Mitochondrial Quality Regulation

Incentives	Related molecules and pathways	Specific mechanisms	References
Oxidative stress	ROS-PINK1/Parkin, Mfn1, Mfn2	The ROS produced by damaged mitochondria reduce mitochondrial membrane potential. PINK1 and Parkin are recruited to the outer membrane of mitochondria to trigger mitophagy	Fan et al. (2019); Rojas-Charry et al. (2014)
	ROS-PINK1/Parkin, Mfn1, Mfn2	Parkin promotes the degradation of mitochondrial fusion proteins (Mfn1 and Mfn2), helping to isolate damaged mitochondria and mitophagy	McLelland et al. (2014); Schofield and Schafer (2021)
	ROS-FOXO3-BNIP3/LC3	ROS initiates the FOXO3 signaling pathway, and FOXO3 regulates the transcription of BNIP3 and LC3, thereby promoting mitophagy	Aucello et al. (2009); Shen et al. (2015)
	ROS-HIF-1-BNIP3/NIX	ROS activates HIF-1, which can promote the transcription of BNIP3 and NIX, thus promoting mitophagy	Klumpen et al. (2017)
	ROS-NRF2-P62	ROS directly activates NRF2, which promotes the expression of P62 mRNA and activates mitophagy	Jain et al. (2010); Rubio et al. (2014)
ERS	PERK/ATF4-Parkin, c-Jun, JNK3	AFT4 (an unfolded protein response transcription factor) and c-Jun competitively bind to specific sites of Parkin promoter, AFT4 can promote Parkin expression and activate mitophagy, but c-Jun has the opposite effect	Bouman et al. (2011)
	Eif2s1-ATF4-Parkin	Silencing of Eif2s1 and downstream ATF4 can reduce the expression of Parkin and weaken mitophagy	Zhang et al. (2014)
	IRE1-TRAF2-JNK pathway	The PERK-eIF2 pathway is unnecessary for ERS-induced autophagy, and activation of the IRE1-TRAF2-JNK pathway is a necessary condition for ERS-induced autophagosome membrane formation	Ogata et al. (2006)
	IRE1-XBP1 pathway	Mild ERS activates the IRE1-XBP1 pathway and induces mitophagy to degrade damaged mitochondria	Thomas et al. (2011); Duplan et al. (2013)
Unfolded proteins	PINK1-Parkin	PINK1 senses the accumulation of misfolded proteins in the mitochondrial matrix, causing the transposition of Parkin to the mitochondria	Imai et al. (2001); Jin and Youle (2013); Runkel et al. (2014); Senft and Ronai (2015)
Ca²⁺	DRP1, OPA1, Mfns	Ca²⁺ accumulated in mitochondria can act on mitochondrial membrane proteins (DRP1, OPA1, and Mfns), thereby increasing mitochondrial membrane permeability and mitochondrial cristae remodeling	Pizzo and Pozzan (2007); Cali et al. (2013); van Vliet et al. (2014)
Inflammation	LC3, Beclin1, NLRP3 inflammasome, IL-1β, IL-18	NLRP3 inflammasome and the release of IL-1β and IL-18 can activate mitophagy. Mitophagy can inhibit NLRP3 inflammasome-mediated mtDNA release, reduce caspase-1 activation and production of IL-1β and IL-18	Nakahira et al. (2011); Yu et al. (2014)
	LC3, Beclin1, NLRP3 inflammasome, IL-1β, IL-18
	NF-κB-p62/SQSTM1, NLRP3 inflammasome	NF-κB restricts inflammasome activation via the elimination of damaged mitochondria	O'Sullivan et al. (2015); Zhong et al. (2016)
	OPA1, Mfn1, Mfn2	Memory T cells have a tighter cristae structure and increased spare respiratory capacity depending on the fusion of the inner and outer membranes of the mitochondria	Buck et al. (2016); Mills et al. (2017)

BNIP3, BCL2/adenovirus E1B 19 kDa interacting protein 3; DRP1, dynamic-related protein 1; ERS, endoplasmic reticulum stress; FOXO3, Forkhead Box O3; HIF, hypoxia-inducible factor; Mfn1, mitofusins 1; Mfn2, mitofusins 2; mtDNA, mitochondrial DNA; NIX/BNIP3L, NIP-3-like protein X; OPA1, optical atrophy 1 protein; p62/SQSTM1, sequestosome-1; PINK1, PTEN-induced putative kinase 1; ROS, reactive oxygen species.

Mitochondrial Quality Control and Diseases

Congenital peripheral neuropathy

Eighteen mitochondrial proteins are encoded by mtDNA, and the nuclear genome encodes the remainder (Nissanka and Moraes, 2018). Most of these proteins are distributed in the bilayer membrane of mitochondria and regulate the mitochondrial network's regular operation together with cytoplasmic proteins transferred to mitochondria (Baloh, 2008).

Mutations of mitochondrial coding genes affect the formation and development of mitochondria and affect the transport, distribution, and function of mitochondria. These mechanisms mediate mitochondrial diseases (a review has been discussed) (Whitley et al., 2019) and congenital peripheral neuropathy.

The most typical disease is gastrocnemius atrophy (Charcot–Marie–Tooth disease type 2A, or CMT2A), caused by the mutation of the Mfn2 gene regulating mitochondrial fusion (Dorn, 2020). Patients may have motor and sensory abnormalities of peripheral nerves such as muscle weakness and atrophy of the lower limbs, mild loss of sensation, or absence of deep tendon reflex; nerve conduction velocities are normal or near normal (Lawson et al., 2005). The pathology of the disease is complex, genetic heterogeneity is high, and the specific pathogenesis is not fully understood.

Studies have shown that the 94 amino acid residue upstream of the GTPase domain of Mfn2 is most prone to mutation, and codons are mutated to R94W and R94Q (Franco et al., 2016). Thus, mitochondrial fusion is inhibited, causing its shape to become spherical or elliptical. These shapes do not readily translocate in axons, affecting the energy production of the axon and the function of synapses and eventually leading to axonal degeneration.

Ueda and Ishihara, (2018) found that Marf (Marf is the Drosophila homolog of Mfn2) mutants in the GTPase domain or mutants in the HB1 region in CMT2A Drosophila model had larger mitochondria in neurons. The authors suggested that some pathogenic mutations of Mfn2 could enhance mitochondrial fusion, indicating that the enhancement of mitochondrial fusion could also lead to pathological changes in CMT2A. Another study found that many hyper-tubular mitochondria in the primary fibroblasts of patients with hereditary spastic paraplegia hindered the transport of mitochondria to the axonal end (Lavie et al., 2017). The reason is that mutations of receptor expression-enhancing protein 1 (REEP1), which encodes tubulin, impair interactions between REEP1 and PGAM5, leading to hyperphosphorylation of mitochondrial fission protein DRP1.

Epigenetic disorders of the proteins that regulate fusion and fission also cause congenital peripheral neuropathy, providing novel insights into the disease's molecular mechanisms and therapeutic targets. Other diseases caused by mitochondrial gene mutations are characterized by central nervous system damage accompanied by peripheral neuropathy (Gao et al., 2017); it is clear that once the balance of mitochondrial fusion and fission is broken, there follows a series of pathological reactions.

Peripheral neuropathy caused by chemotherapeutic agents

Chemotherapy-induced peripheral neuropathy (CIPN) is a profound dose-dependent toxic side effect of many anti-cancer medications. These chemotherapeutic agents include platinum compounds, taxanes, and vinca alkaloids (Jaggi and Singh, 2012; Carozzi et al., 2015). The most common clinical symptoms are glove-and-sock-like paresthesias (Pulvers and Marx, 2017). In more severe cases, neuropathic pain may occur (Kerckhove et al., 2017). The mechanisms of CIPN include changes in ion channels, increased apoptosis, and the release of inflammatory cytokines (Starobova and Vetter, 2017).

Chemotherapeutic agents have a tendency to accumulate in the dorsal root ganglion (DRG) and form adducts with mtDNA, leading to mitochondrial damage and the release of a large amount of ROS (Trecarichi and Flatters, 2019). Therefore, mitochondrial dysfunction and oxidative stress are other prominent causes of CIPN and peripheral nerve pain (Waseem et al., 2018).

Some central degenerative diseases, such as Parkinson's disease, the pathogenesis is mitochondrial dysfunction caused by PINK1 and Parkin mutations leading to the loss of substantia nigra dopaminergic neurons (Dar et al., 2020; Malpartida et al., 2021). As for CIPN, people have also found that mitochondrial damage and oxidative stress can cause neuropathy (Lim et al., 2015; Rumora et al., 2019; Trecarichi and Flatters, 2019). Therefore, investigators further conjectured the relationships between mitochondrial quality control and CIPN and experimented to obtain meaningful results.

Kober et al. (2018) measured the expression of mitochondrial genes involved in peripheral neuropathy in the peripheral blood of breast cancer survivors receiving paclitaxel chemotherapy; the authors found that mitochondrial fission-related genes were linked to peripheral nerve pain. The same phenomenon was also noted in primary mouse DRG cells treated with vincristine, with reduced mitochondrial fusion and, to a lesser extent, mitophagy (Chen et al., 2020).

In another study, Drosophila larvae were treated with paclitaxel to induce peripheral neuropathy. Overexpression of PINK1 in class IV dendritic branched sensory neurons improved thermal hyperalgesia of the model, whereas PINK1 knockout led to an increase in thermal hyperalgesia (Kim et al., 2020). Nevertheless, the molecular mechanisms of these phenomena have not been elucidated.

After knocking down parkin in PC12 (a rat pheochromocytoma cell line) and treating with cisplatin, Zhang et al. (2019) found that the toxicity of cisplatin to PC12 increased, which was primarily owing to the damage of PINK1/parkin mitochondrial autophagy pathway, resulting in mitochondrial dysfunction, ATP deficiency, and ROS burst, eventually increasing apoptosis; overexpression of parkin enhanced mitochondrial autophagy and reversed the damage. Song and colleagues used tricresol phosphate (TOCP) to treat Neuro-2a (N2a, a mouse neuroblastoma cell line) to mimic organophosphate-induced delayed neuropathy, showing that TOCP activated the PINK1/parkin-mediated mitochondrial autophagy pathway in N2a cells, and the protein p62 was identified as the mitochondrial autophagy adapter (Wang et al., 2019).

The inhibition of mitochondrial autophagy in gastrocnemius muscle after sciatic nerve transection in mice improved symptoms of paralysis in that muscle (Graham et al., 2018), suggesting that mitochondrial dysfunction may be the common pathogenic mechanism of peripheral neuropathy caused by chemotherapeutic agents and other toxic drugs. Whether mitophagy mediated by PINK1/Parkin plays a protective role may be related to the type of histopathology and severity. More preclinical trials are needed to determine whether the damaging medications activate ubiquitin-mediated mitophagy, whether the adapters are the same, and through what mitochondrial mechanism autophagy alleviates chemotherapy-induced peripheral neuropathic pain.

Diabetic peripheral neuropathy

Diabetic polyneuropathy (DPN) is the most common chronic complication of diabetes mellitus (Feldman et al., 2017). The underlying mechanisms of DPN have various pathways, including the polyol pathway, the deposition of advanced glycosylation products, the hexosamine pathway, and the protein kinase C pathway (Ceriello, 2003; Sifuentes-Franco et al., 2017). The final common endpoint is that oxidative stress, nitrosation stress, and the reduction of neuronal antioxidant defense mechanisms lead to diseases (Bandeira et al., 2013; Stavniichuk et al., 2014). The signs and symptoms of DPN include decreased blood flow to supplying nerves, anoxia of the endoneurium, degeneration of motor nerves, loss of sensation, and neuropathic pain (Llewelyn, 2003; Peltier et al., 2014; Wang et al., 2014).

Several studies noted that mitochondrial quality control participates in DPN, and regulating the expression of mitochondrial quality control-related proteins effectively inhibits DPN development and alleviates the peripheral nerve pain caused by diabetes.

Yoon and colleagues found that the morphology of mitochondria was tied to ROS content after high-glucose treatment, and inhibition of mitochondrial division reduced ROS production (Yu et al., 2006). The same conclusion was reached in a subsequent experiment in which primary rat DRG cells were cultured with high-glucose in vitro; it was also demonstrated that high glucose increased the expression of mitochondrial fission protein DRP1 and the colocalization of DRP1 and Bax, suggesting that the interaction between mitochondrial fission and apoptosis leads to DPN (Leinninger et al., 2006). However, the apoptosis pathway of DRP1/Bax is different from that of BIM/Bax (Leinninger et al., 2006).

In a recent study, in a mouse model of type I diabetes, the upregulation of p53 in the ruined DRG inhibited the transcription of Parkin (Yamashita et al., 2019). The subsequent disruption of Parkin-mediated mitochondrial quality control mechanism led to ROS accumulation and ultimately to DPN and diabetic neuropathic pain (Yamashita et al., 2019). The process could be reversed using p53 selective inhibitors, consistent with the negative regulation of p53 on Parkin in cultured cortical neurons in vitro (da Costa et al., 2009).

Although investigators have long recognized that mitochondrial dysfunction is the pathogenic mechanism of DPN, the similarities and differences between mitochondrial quality control in types 1 and 2 diabetes have not yet been conclusively established, and targeted medications for mitochondrial quality control need to be further explored.

Treatment

At present, treatment of peripheral neuropathy focuses on the cure of primary disease or alleviating symptoms; there is no definitive treatment. With the in-depth exploration of the mitochondrial quality control mechanism and its relationship with peripheral neuropathy, some new therapeutic agents and methods have been explored. Some medications that have been used clinically for other indications can be used to treat peripheral neuropathy by regulating mitochondrial quality control. Because each disease causes different mitochondrial quality control disorders, the treatment methods are different. According to existing preclinical experiments, treatment methods include gene therapy, drug therapy (peptides, agonists/inhibitors, mitochondrially targeted drugs, antioxidants), and physical therapy (Table 2).

Table 2.

List of Methods to Treat Peripheral Neuropathy by Regulating Mitochondrial Quality

Therapies		Diseases	Typical drugs/technologies	Animal/cell models	Mechanisms	References
Gene therapy		SLC25A46-related mitochondrial disorders	AAV-Slc25a46	Mice (Slc25a46^−/− )	The gene-Slc25a46 is carried by AAV-PHP.B vector and given intravenously, and the morphology of mitochondria in the peripheral nerve returned to normal and the activity of mitochondrial complex was restored	Yang et al. (2020)
Gene therapy		CMT2A	Transgenic technology	Thy1.2-Mfn2^R94Q mice	Generated Prp-Mfn1 mice expressing Flag-tagged human Mfn1 under the PrP promoter and crossed with Thy1.2-Mfn2^R94Q mice to generate the double-transgenic (Mfn2^R94Q:Mfn1) mice; expression of Mfn1 in the nervous system rescued the stunted growth and reduced survival	Zhou et al. (2019)
Drug therapy	Peptides	CMT2A	HR1 minipeptides	Cultured fibroblasts; rat neurons harboring CMT2A gene defects	Destabilized fusion-constrained mitofusin and promoted the fusion-permissive conformation to reverse mitochondrial abnormalities	Franco et al. (2016)
	Peptides	Type 1 DPN	IGF-1	STZ-induced type 1 diabetic rats	Elevated AMPK and P70S6K phosphorylation; raised Complex IV and V expression; reversed thermal hypoalgesia	Aghanoori et al. (2019)
	Agonists/inhibitors	CMT2A	Mfn2 agonist (mitomycin agonist, 6-phenylhexanamide derivatives)	HB9-Cre/Mfn2 T105M CMT2A mice; Mfn1- or Mfn2-deficient MEFs	Enhanced the probability of trans Mfn-Mfn dimer formation between mitochondria and facilitated mitochondrial tethering/fusion	Rocha et al. (2018); Dang et al. (2020)
	Agonists/inhibitors	CMT2A	HDAC6 inhibitor (SW-100)	HDAC6 null mice (C57BL/6-HDAC6-/y); Mfn2^R94Q mice	HDAC6 was the target for ameliorating the CMT2A phenotype; SW-100 restored α-tubulin acetylation and ameliorated motor and sensory dysfunction	Picci et al. (2020)
	Mitochondrial-targeted drugs	CIPN	MT	CCI mice	Increased Mfn1 and OPA1 and decreased expression of DRP1 and Fis1, relieving neuropathic pain by protecting mitochondria against oxidative stress injury	Rappold et al. (2014); Zhan et al. (2018)
	Mitochondrial-targeted drugs	CIPN	MitoQ	Vincristine-induced peripheral neuropathy mice; primary neuron from mice lumbar dorsal root ganglia	Inhibited the expression of DRP1 and FIS to enhance mitochondrial fusion and the process of Cyto-c release from mitochondria to improve mitochondrial dysfunction; relieved peripheral nerve pain	Yan et al. (2015); Chen et al. (2020)
	Non-mitochondrial-targeted antioxidants	Oxaliplatin-induced peripheral neuropathy	Melatonin	Oxaliplatin-induced peripheral neuropathy; N2a cell	Enhanced mitophagy, relieved oxidative stress, and saved mitochondrial function; relieved peripheral nerve pain	Areti et al. (2017)
	Non-mitochondrial-targeted antioxidants	Oxaliplatin-induced peripheral neuropathy	Tanshinone IIA	Oxaliplatin-induced peripheral neuropathy; N2a cell	Promoted mitophagy through the PI3K/Akt/mTOR signaling pathway, improved mitochondrial membrane potential, relieving peripheral nerve pain	Cheng et al. (2019)
Physical therapy		CIPN	HBOT	CCI rat	CaMKKβ/AMPK pathway maybe a potential signal pathway on analgesic mechanism via mitophagy	Han et al. (2017); Kun et al. (2019)

AAV, adeno-associated virus; CCI, chronic constriction injury; CIPN, chemotherapy-induced peripheral neuropathy; CMT2A, Charcot–Marie–Tooth disease type 2A; DPN, diabetic polyneuropathy; Fis1, fission protein 1; HBOT, hyperbaric oxygen therapy; HDAC6, histone deacetylase 6; IGF-1, insulin-like growth factor 1; MEFs, murine embryonic fibroblasts; MitoQ, mitoquinone; MT, mito-TEMPO; N2a, neuro-2a; Prp, prion protein; STZ, streptozotocin.

Gene therapy

Some cases of congenital peripheral neuropathy are caused by mutations in genes encoding mitochondrial proteins. Therefore, gene therapy for mutated genes is a fundamental treatment. SLC25A46 is a mitochondrial protein encoded by the nuclear genome; its deletion leads to mitochondrial hyperfusion and causes ataxia. Huang et al. packaged Slc25a46 with adeno-associated virus (AAV) and injected it into Slc25a46^−/− mice circulation (Yang et al., 2020). As a result, mitochondrial dynamics were restored, and the function of the respiratory chain improved.

Peripheral neuropathy caused by mutations in a single mtDNA or nucleus-encoded mitochondrial gene can be considered for gene-targeted therapy. AAV-mediated gene therapy in vivo has high transduction efficiency (Colella et al., 2018), and successfully applied in degenerative neuropathy (Piguet et al., 2017; Perez et al., 2020). However, there are few studies on AAV-mediated gene therapy of congenital peripheral neuropathy in vivo, and its effective gene targets and immunogenicity are even more challenging (Verdera et al., 2020).

Baloh and colleagues used transgenic technology to express Mfn1 in the nervous system of Mfn2^R94Q mice, which not only rescued the stunted growth but also increased their survival rate (Zhou et al., 2019). Their experiments also proved that the Mfn1/Mfn2 ratio is a crucial determinant of the tissue specificity of CMT2A, and Mfn1 is the treatment target (Zhou et al., 2019). This provides a theoretical basis for the application of gene therapy CMT2A.

Drug therapy

Peptides

Scientists have invented some peptides that can enter the cell to regulate the interaction between molecules and then change the protein conformation to achieve treatment (Barbullushi et al., 2019). Rocha et al. (2018) used HR1 minipeptides to make Mfn2 a definitive transition to the fusion-permissive conformation (Franco et al., 2016). and reversed the mitochondrial axon transport disorder in the sciatic nerve of CMT2A mice. For streptozotocin (STZ)-induced type 1 diabetic rats, Paul Aghanoori believes that insulin-like growth factor 1 (IGF-1) can restore mitochondrial dysfunction and relieve peripheral nerve pain (Aghanoori et al., 2019). But there are no experiments to point out the difference between mitochondrial quality control disorders in type 1 and type 2 diabetes, and there are no specific drugs to alleviate DPN.

Agonists/inhibitors

Recently, Mfn2 and histone deacetylase 6 (HDAC6) have become research hotspots in the pathogenesis of CMT2A. Gerald W. Dorn II and others successfully used Mfn2 agonist (also a mitomycin receptor agonist) to promote the trans-Mfn-Mfn dimer formation and promote mitochondrial fusion in vivo and in vitro (Rocha et al., 2018; Dang et al., 2020). Another study used HDAC6 inhibitor (SW-100) to restore α-tubulin acetylation and improved mice's motor and sensory dysfunction (Picci et al., 2020). It puts forward that HDAC6 is a target to ameliorate the CMT2A phenotype and provides new ideas for applying epigenetics in the treatment of CMT2A.

Mitochondrial-targeted drugs and nonmitochondrial-targeted antioxidants

The efficacy of mito-TEMPO, a mitochondrial-targeted drug, was demonstrated in a variety of pathological types (Liu et al., 2018b; Shetty et al., 2019). It inhibits oxidative stress by increasing the content of reduced glutathione and enhancing total superoxide dismutase activity. One study found that mito-TEMPO enhanced the expression of mitochondrial fusion genes and inhibited the expression of fission genes, and alleviated peripheral neuralgia in a rat model of chronic constriction injury (CCI) (Zhan et al., 2018).

Mitoquinone (MitoQ), an anti-neoplastic agent, enhanced mitochondrial fusion genes' expression, inhibited fission genes' expression, and alleviated vincristine-induced pain in mice (Chen et al., 2020). Melatonin, tanshinone IIA, salidroside, and other nonmitochondrial-targeted antioxidants enhanced ubiquitin-mediated mitochondrial autophagy (Areti et al., 2017; Li and Chen, 2019; Gu et al., 2020). They alleviated CIPN pain without causing deterioration of the original tumor in vivo and in vitro studies (Areti et al., 2017). But nowadays, there are few reports about antioxidants regulating mitochondrial dynamics to treat peripheral neuropathy, and no medication combinations have been reported to regulate mitochondrial quality control.

Physical therapy

Hyperbaric oxygen therapy (HBOT) is 100% oxygen breathing in a pressure vessel above atmospheric pressure, a well-established treatment for various conditions (Memar et al., 2019). HBOT has been proven effective in treating carbon monoxide poisoning, crush injuries, and infections. It has also been reported that HBOT can reduce neuromuscular damage (Moghadam et al., 2020). Some people have observed that HBOT can regulate mitochondrial autophagy to reduce pain in CCI rats (Han et al., 2017; Kun et al., 2019), but how HBOT can regulate peripheral nerve mitochondrial quality needs to be further explored.

Conclusions and Outlook

Peripheral neuropathy is related to the patient's quality of life and psychology (Seretny et al., 2014), so it has always been the medical community's focus (Barrell and Smith, 2019). Both mitophagy and mitochondrial dynamics are indispensable in maintaining the normal physiological functions of peripheral nerves, and they are also an essential link in the pathogenesis of peripheral neuropathy.

The relationship between mitochondrial dysfunction and peripheral neuropathy has been identified. Beneficial mitochondrial quality regulation can eliminate dysfunctional mitochondria to achieve the purpose of treatment, but there is no uniform and specific medicine or method for the treatment of peripheral neuropathy (Derksen et al., 2017). For congenital peripheral neuropathy, the better solution would be to couple gene therapy and peptides, meaning that the treatment should address both replacing the gene and stabilizing gene expression product conformation (Barbullushi et al., 2019). For noncongenital peripheral neuropathy, such as CIPN or DPN, mitochondrial-targeted drugs and nonmitochondrial-targeted antioxidants can be combined, or maybe medication and physical therapy can be combined.

In short, more preclinical experiments are needed to prove the feasibility and safety of the combination therapy. The mechanism of mitochondrial quality regulation remains to be explored, and it is expected to become an essential target for the treatment of peripheral neuropathy.

Footnotes

Authors' Contributions

T.Z. participated in original draft and figure preparation. J.L. participated in the structured outline preparation and the article revising. T.Z. participated in the article revising. G.Z. participated in the conception of the review and the final revision of the article.

Acknowledgment

We thank Robert P. Lindeman, MD, PhD, for editing and proofreading this review.

Disclosure Statement

The authors have no potential conflicts of interest to disclose.

Funding Information

This work was supported by the National Natural Science Foundation of China (Grant No. 81903273, to G.Z.). The funding sources had no role in study conception and design, data analysis, or interpretation, article writing or deciding to submit this article for publication.

References

Abe

, Shodai

, Muto

, Mihara

, Torii

, Nishikawa

, et al. (2000). Structural basis of presequence recognition by the mitochondrial protein import receptor Tom20. Cell, 100, 551–560.

Aghanoori

M.-R.

, Smith

D.R.

, Shariati-Ievari

, Ajisebutu

, Nguyen

, Desmond

, et al. (2019). Insulin-like growth factor-1 activates AMPK to augment mitochondrial function and correct neuronal metabolism in sensory neurons in type 1 diabetes. Mol Metab, 20, 149–165.

Alexander

, Votruba

, Pesch

U.E.

, Thiselton

D.L.

, Mayer

, Moore

, et al. (2000). OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet, 26, 211–215.

Amadoro

, Corsetti

, Florenzano

, Atlante

, Bobba

, Nicolin

, et al. (2014). Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons: the pink-parkin pathway. Front Aging Neurosci, 6, 18.

Areti

, Komirishetty

, Akuthota

, Malik

R.A.

, and Kumar

(2017). Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy. J Pineal Res, 62, 1–17.

Ashrafi

, and Schwarz

T.L.

(2013). The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ, 20, 31–42.

Aucello

, Dobrowolny

, and Musaro

(2009). Localized accumulation of oxidative stress causes muscle atrophy through activation of an autophagic pathway. Autophagy, 5, 527–529.

Baloh

R.H.

(2008). Mitochondrial dynamics and peripheral neuropathy. Neuroscientist, 14, 12–18.

Bandeira

S.M.

, da Fonseca

L.J.S.

, Guedes

G.S.

, Rabelo

L.A.

, Goulart

M.O.F.

, and Vasconcelos

S.M.L.

(2013). Oxidative stress as an underlying contributor in the development of chronic complications in diabetes mellitus. Int J Mol Sci, 14, 3265–3284.

10.

Barbullushi

, Abati

, Rizzo

, Bresolin

, Comi

G.P.

, and Corti

(2019). Disease modeling and therapeutic strategies in CMT2A: state of the art. Mol Neurobiol, 56, 6460–6471.

11.

Barrell

, and Smith

A.G.

(2019). Peripheral neuropathy. Med Clin North Am, 103, 383–397.

12.

Bingol

, and Sheng

(2016). Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond. Free Radic Biol Med, 100, 210–222.

13.

Bouman

, Schlierf

, Lutz

A.K.

, Shan

, Deinlein

, Kast

, et al. (2011). Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ, 18, 769–782.

14.

Buck

M.D.

, O'Sullivan

, Klein Geltink

R.I.

, Curtis

J.D.

, Chang

C.H.

, Sanin

D.E.

, et al. (2016). Mitochondrial dynamics controls T cell fate through metabolic programming. Cell, 166, 63–76.

15.

Cali

, Ottolini

, Negro

, and Brini

(2013). Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca(2+) transfer to sustain cell bioenergetics. Biochim Biophys Acta, 1832, 495–508.

16.

Carozzi

V.A.

, Canta

, and Chiorazzi

(2015). Chemotherapy-induced peripheral neuropathy: what do we know about mechanisms?. Neurosci Lett, 596, 90–107.

17.

Ceriello

(2003). New insights on oxidative stress and diabetic complications may lead to a “causal”. antioxidant therapy. Diabetes Care, 26, 1589–1596.

18.

Chan

D.C.

(2020). Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol, 15, 235–259.

19.

Chandhok

, Lazarou

, and Neumann

(2018). Structure, function, and regulation of mitofusin-2 in health and disease. Biol Rev Camb Philos Soc, 93, 933–949.

20.

Chen

, Han

, Feng

, Chen

, Wu

, et al. (2014). A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol Cell, 54, 362–377.

21.

Chen

, Chen

, Wang

, Tan

, Zhu

, Li

, et al. (2016). Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy, 12, 689–702.

22.

Chen

X.-J.

, Wang

, and Song

X.-Y.

(2020). Mitoquinone alleviates vincristine-induced neuropathic pain through inhibiting oxidative stress and apoptosis via the improvement of mitochondrial dysfunction. Biomed Pharmacother, 125, 110003.

23.

Cheng

, Xiang

, Wang

, and Xu

(2019). Tanshinone IIA ameliorates oxaliplatin-induced neurotoxicity via mitochondrial protection and autophagy promotion. Am J Transl Res, 11, 3140–3149.

24.

Chinnadurai

, Vijayalingam

, and Gibson

S.B.

(2008). BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions. Oncogene, 27(Suppl 1), S114–S127.

25.

Chung

Y.C.

, Lim

J.H.

, Oh

H.M.

, Kim

H.W.

, Kim

M.Y.

, Kim

E.N.

, et al. (2018). Calcimimetic restores diabetic peripheral neuropathy by ameliorating apoptosis and improving autophagy. Cell Death Dis, 9, 1163.

26.

Cipolat

, Martins de Brito

, Dal Zilio

, and Scorrano

(2004). OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A, 101, 15927–15932.

27.

Cogliati

, Frezza

, Soriano

M.E.

, Varanita

, Quintana-Cabrera

, Corrado

, et al. (2013). Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell, 155, 160–171.

28.

Colella

, Ronzitti

, and Mingozzi

(2018). Emerging issues in AAV-mediated gene therapy. Mol Ther Methods Clin Dev, 8, 87–104.

29.

da Costa

C.A.

, Sunyach

, Giaime

, West

, Corti

, Brice

, et al. (2009). Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. Nat Cell Biol, 11, 1370–1375.

30.

Dang

, Zhang

, Franco

, Li

, Rocha

A.G.

, Devanathan

, et al. (2020). Discovery of 6-phenylhexanamide derivatives as potent stereoselective mitofusin activators for the treatment of mitochondrial diseases. J Med Chem, 63, 7033–7051.

31.

Dar

K.B.

, Bhat

A.H.

, Amin

, Reshi

B.A.

, Zargar

M.A.

, Masood

, et al. (2020). Elucidating critical proteinopathic mechanisms and potential drug targets in neurodegeneration. Cell Mol Neurobiol, 40, 313–345.

32.

Deas

, Plun-Favreau

, Gandhi

, Desmond

, Kjaer

, Loh

S.H.Y.

, et al. (2011). PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet, 20, 867–879.

33.

Derksen

T.M.E.

, Bours

M.J.L.

, Mols

, and Weijenberg

M.P.

(2017). Lifestyle-related factors in the self-management of chemotherapy-induced peripheral neuropathy in colorectal cancer: a systematic review. Evid Based Complement Alternat Med, 2017, 7916031.

34.

Dikic

, and Elazar

(2018). Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol, 19, 349–364.

35.

Ding

W.-X.

, and Yin

X.-M.

(2012). Mitophagy: mechanisms, pathophysiological roles, and analysis. Biol Chem, 393, 547–564.

36.

Dorn

G.W.

(2020). Mitofusin 2 dysfunction and disease in mice and men. Front Physiol, 11, 782.

37.

Duplan

, Giaime

, Viotti

, Sevalle

, Corti

, Brice

, et al. (2013). ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1. J Cell Sci, 126, 2124–2133.

38.

Durcan

T.M.

, and Fon

E.A.

(2015). The three ‘P's of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes Dev, 29, 989–999.

39.

Eiyama

, and Okamoto

(2015). PINK1/Parkin-mediated mitophagy in mammalian cells. Curr Opin Cell Biol, 33, 95–101.

40.

El-Hattab

A.W.

, Suleiman

, Almannai

, and Scaglia

(2018). Mitochondrial dynamics: biological roles, molecular machinery, and related diseases. Mol Genet Metab, 125, 315–321.

41.

Fan

, Xie

X.H.

, Chen

C.H.

, Peng

, Zhang

, Yang

, et al. (2019). Molecular regulation mechanisms and interactions between reactive oxygen species and mitophagy. DNA Cell Biol, 38, 10–22.

42.

Feldman

E.L.

, Nave

K.-A.

, Jensen

T.S.

, and Bennett

D.L.H.

(2017). New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. Neuron, 93, 1296–1313.

43.

Feng

, Liu

, Zhu

, and Chen

(2013). Molecular signaling toward mitophagy and its physiological significance. Exp Cell Res, 319, 1697–1705.

44.

Flatters

S.J.

(2015). The contribution of mitochondria to sensory processing and pain. Prog Mol Biol Transl Sci, 131, 119–146.

45.

Flippo

K.H.

, and Strack

(2017). Mitochondrial dynamics in neuronal injury, development and plasticity. J Cell Sci, 130, 671–681.

46.

Franco

, Kitsis

R.N.

, Fleischer

J.A.

, Gavathiotis

, Kornfeld

O.S.

, Gong

, et al. (2016). Correcting mitochondrial fusion by manipulating mitofusin conformations. Nature, 540, 74–79.

47.

Gao

, Wang

, Liu

, Xie

, Su

, and Wang

(2017). Abnormalities of mitochondrial dynamics in neurodegenerative diseases. Antioxidants (Basel), 6, 25.

48.

Geisler

, Holmström

K.M.

, Skujat

, Fiesel

F.C.

, Rothfuss

O.C.

, Kahle

P.J.

, et al. (2010). PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol, 12, 119–131.

49.

Graham

Z.A.

, Harlow

, Bauman

W.A.

, and Cardozo

C.P.

(2018). Alterations in mitochondrial fission, fusion, and mitophagic protein expression in the gastrocnemius of mice after a sciatic nerve transection. Muscle Nerve, 58, 592–599.

50.

Greene

A.W.

, Grenier

, Aguileta

M.A.

, Muise

, Farazifard

, Haque

M.E.

, et al. (2012). Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep, 13, 378–385.

51.

Griffin

E.E.

, and Chan

D.C.

(2006). Domain interactions within Fzo1 oligomers are essential for mitochondrial fusion. J Biol Chem, 281, 16599–16606.

52.

, Li

, Huang

, Qian

, Liu

, Zhang

, et al. (2020). Salidroside ameliorates mitochondria-dependent neuronal apoptosis after spinal cord ischemia-reperfusion injury partially through inhibiting oxidative stress and promoting mitophagy. Oxid Med Cell Longev, 2020, 3549704.

53.

Han

, Liu

, Li

, and Zhao

(2017). The effects of hyperbaric oxygen therapy on neuropathic pain via mitophagy in microglia. Mol Pain, 13, 1744806917710862.

54.

Hanna

R.A.

, Quinsay

M.N.

, Orogo

A.M.

, Giang

, Rikka

, and Gustafsson

Å.B.

(2012). Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J Biol Chem, 287, 19094–19104.

55.

Imai

, Soda

, Inoue

, Hattori

, Mizuno

, and Takahashi

(2001). An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell, 105, 891–902.

56.

Ino

, and Iino

(2017). Schwann cell mitochondria as key regulators in the development and maintenance of peripheral nerve axons. Cell Mol Life Sci, 74, 827–835.

57.

Jaggi

A.S.

, and Singh

(2012). Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy. Toxicology, 291, 1–9.

58.

Jain

, Lamark

, Sjottem

, Larsen

K.B.

, Awuh

J.A.

, Overvatn

, et al. (2010). p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem, 285, 22576–22591.

59.

James

D.I.

, Parone

P.A.

, Mattenberger

, and Martinou

J.-C.

(2003). hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem, 278, 36373–36379.

60.

Jin

S.M.

, Lazarou

, Wang

, Kane

L.A.

, Narendra

D.P.

, and Youle

R.J.

(2010). Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol, 191, 933–942.

61.

Jin

S.M.

, and Youle

R.J.

(2013). The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autophagy, 9, 1750–1757.

62.

Kalia

, Wang

R.Y.-R.

, Yusuf

, Thomas

P.V.

, Agard

D.A.

, Shaw

J.M.

, et al. (2018). Structural basis of mitochondrial receptor binding and constriction by DRP1. Nature, 558, 401–405.

63.

Kerckhove

, Collin

, Condé

, Chaleteix

, Pezet

, and Balayssac

(2017). Long-term effects, pathophysiological mechanisms, and risk factors of chemotherapy-induced peripheral neuropathies: a comprehensive literature review. Front Pharmacol, 8, 86.

64.

Kim

D.I.

, Lee

K.H.

, Gabr

A.A.

, Choi

G.E.

, Kim

J.S.

, Ko

S.H.

, et al. (2016). Aβ-induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis. Biochim Biophys Acta, 1863, 2820–2834.

65.

Kim

, Park

, Kim

, Song

, Kwon

S.-K.

, Lee

S.-H.

, et al. (2008). PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun, 377, 975–980.

66.

Kim

Y.Y.

, Yoon

J.-H.

, Um

J.-H.

, Jeong

D.J.

, Shin

D.J.

, Hong

Y.B.

, et al. (2020). PINK1 alleviates thermal hypersensitivity in a paclitaxel-induced Drosophila model of peripheral neuropathy. PLoS One, 15, e0239126.

67.

Klumpen

, Hoffschroer

, Zeis

, Gigengack

, Dohmen

, and Paul

R.J.

(2017). Reactive oxygen species (ROS) and the heat stress response of Daphnia pulex: ROS-mediated activation of hypoxia-inducible factor 1 (HIF-1) and heat shock factor 1 (HSF-1) and the clustered expression of stress genes. Biol Cell, 109, 39–64.

68.

Kober

K.M.

, Olshen

, Conley

Y.P.

, Schumacher

, Topp

, Smoot

, et al. (2018). Expression of mitochondrial dysfunction-related genes and pathways in paclitaxel-induced peripheral neuropathy in breast cancer survivors. Mol Pain, 14, 1744806918816462.

69.

Kondapalli

, Kazlauskaite

, Zhang

, Woodroof

H.I.

, Campbell

D.G.

, Gourlay

, et al. (2012). PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol, 2, 120080.

70.

Koyano

, Okatsu

, Kosako

, Tamura

, Go

, Kimura

, et al. (2014). Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature, 510, 162–166.

71.

Kulathu

, and Komander

(2012). Atypical ubiquitylation—the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat Rev Mol Cell Biol, 13, 508–523.

72.

Kun

, Lu

, Yongda

, Xingyue

, and Guang

(2019). Hyperbaric oxygen promotes mitophagy by activating CaMKK/AMPK signal pathway in rats of neuropathic pain. Mol Pain, 15, 1744806919871381.

73.

Lavie

, Serrat

, Bellance

, Courtand

, Dupuy

J.-W.

, Tesson

, et al. (2017). Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation. Hum Mol Genet, 26, 674–685.

74.

Lawson

V.H.

, Graham

B.V.

, and Flanigan

K.M.

(2005). Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology, 65, 197–204.

75.

Lazarou

, Jin

S.M.

, Kane

L.A.

, and Youle

R.J.

(2012). Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev Cell, 22, 320–333.

76.

Lazarou

, Sliter

D.A.

, Kane

L.A.

, Sarraf

S.A.

, Wang

, Burman

J.L.

, et al. (2015). The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature, 524, 309–314.

77.

Leinninger

G.M.

, Backus

, Sastry

A.M.

, Yi

Y.-B.

, Wang

C.-W.

, and Feldman

E.L.

(2006). Mitochondria in DRG neurons undergo hyperglycemic mediated injury through Bim, Bax and the fission protein Drp1. Neurobiol Dis, 23, 11–22.

78.

Lemasters

J.J.

(2005). Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res, 8, 3–5.

79.

, and Chen

(2019). Salidroside protects dopaminergic neurons by enhancing PINK1/Parkin-mediated mitophagy. Oxid Med Cell Longev, 2019, 9341018.

80.

Lim

T.K.Y.

, Rone

M.B.

, Lee

, Antel

J.P.

, and Zhang

(2015). Mitochondrial and bioenergetic dysfunction in trauma-induced painful peripheral neuropathy. Mol Pain, 11, 58.

81.

Liu

, Feng

, Chen

, Zheng

, Song

, et al. (2012). Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol, 14, 177–185.

82.

Liu

, Sakakibara

, Chen

, and Okamoto

(2014). Receptor-mediated mitophagy in yeast and mammalian systems. Cell Res, 24, 787–795.

83.

Liu

, Duan

, Fang

, Shang

, and Tong

(2018a). Mitochondrial protein import regulates cytosolic protein homeostasis and neuronal integrity. Autophagy, 14, 1293–1309.

84.

Liu

, Wang

, Ding

, and Wang

(2018b). Mito-TEMPO alleviates renal fibrosis by reducing inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress. Oxid Med Cell Longev, 2018, 5828120.

85.

Llewelyn

J.G.

(2003). The diabetic neuropathies: types, diagnosis and management. J Neurol Neurosurg Psychiatry, 74(Suppl 2), ii15-ii19.

86.

, Chen

, Li

, Kepp

, Zhu

, and Chen

(2020). Mitophagy, mitochondrial homeostasis, and cell fate. Front Cell Dev Biol, 8, 467.

87.

Malpartida

A.B.

, Williamson

, Narendra

D.P.

, Wade-Martins

, and Ryan

B.J.

(2021). Mitochondrial dysfunction and mitophagy in Parkinson's disease: from mechanism to therapy. Trends Biochem Sci, 46, 329–343.

88.

McLelland

G.L.

, Soubannier

, Chen

C.X.

, McBride

H.M.

, and Fon

E.A.

(2014). Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J, 33, 282–295.

89.

Meeusen

, McCaffery

J.M.

, and Nunnari

(2004). Mitochondrial fusion intermediates revealed in vitro. Science, 305, 1747–1752.

90.

Meissner

, Lorenz

, Weihofen

, Selkoe

D.J.

, and Lemberg

M.K.

(2011). The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J Neurochem, 117, 856–867.

91.

Memar

M.Y.

, Yekani

, Alizadeh

, and Baghi

H.B.

(2019). Hyperbaric oxygen therapy: antimicrobial mechanisms and clinical application for infections. Biomed Pharmacother, 109, 440–447.

92.

Meyer

J.N.

, Leuthner

T.C.

, and Luz

A.L.

(2017). Mitochondrial fusion, fission, and mitochondrial toxicity. Toxicology, 391, 42–53.

93.

Mills

E.L.

, Kelly

, and O'Neill

L.A.J.

(2017). Mitochondria are the powerhouses of immunity. Nat Immunol, 18, 488–498.

94.

Mishra

, and Chan

D.C.

(2016). Metabolic regulation of mitochondrial dynamics. J Cell Biol, 212, 379–387.

95.

Moghadam

, Hieda

, Ramey

, Levine

B.D.

, and Guilliod

(2020). Hyperbaric oxygen therapy in sports musculoskeletal injuries. Med Sci Sports Exerc, 52, 1420–1426.

96.

Nakahira

, Haspel

J.A.

, Rathinam

V.A.

, Lee

S.J.

, Dolinay

, Lam

H.C.

, et al. (2011). Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol, 12, 222–230.

97.

Narendra

D.P.

, Jin

S.M.

, Tanaka

, Suen

D.-F.

, Gautier

C.A.

, Shen

, et al. (2010). PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol, 8, e1000298.

98.

Nguyen

T.N.

, Padman

B.S.

, and Lazarou

(2016). Deciphering the molecular signals of PINK1/Parkin mitophagy. Trends Cell Biol, 26, 733–744.

99.

H.M.

, Williams

J.A.

, and Ding

W.X.

(2015). Mitochondrial dynamics and mitochondrial quality control. Redox Biol, 4, 6–13.

100.

Nissanka

, and Moraes

C.T.

(2018). Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease. FEBS Lett, 592, 728–742.

101.

Novak

, Kirkin

, McEwan

D.G.

, Zhang

, Wild

, Rozenknop

, et al. (2010). Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep, 11, 45–51.

102.

O'Sullivan

T.E.

, Johnson

L.R.

, Kang

H.H.

, and Sun

J.C.

(2015). BNIP3- and BNIP3L-mediated mitophagy promotes the generation of natural killer cell memory. Immunity, 43, 331–342.

103.

Ogata

, Hino

, Saito

, Morikawa

, Kondo

, Kanemoto

, et al. (2006). Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol, 26, 9220–9231.

104.

Okatsu

, Koyano

, Kimura

, Kosako

, Saeki

, Tanaka

, et al. (2015). Phosphorylated ubiquitin chain is the genuine Parkin receptor. J Cell Biol, 209, 111–128.

105.

Olichon

, Baricault

, Gas

, Guillou

, Valette

, Belenguer

, et al. (2003). Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem, 278, 7743–7746.

106.

Olichon

, Emorine

L.J.

, Descoins

, Pelloquin

, Brichese

, Gas

, et al. (2002). The human dynamin-related protein OPA1 is anchored to the mitochondrial inner membrane facing the inter-membrane space. FEBS Lett, 523, 171–176.

107.

Ordureau

, Heo

J.-M.

, Duda

D.M.

, Paulo

J.A.

, Olszewski

J.L.

, Yanishevski

, et al. (2015). Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy. Proc Natl Acad Sci U S A, 112, 6637–6642.

108.

Ordureau

, Sarraf

S.A.

, Duda

D.M.

, Heo

J.-M.

, Jedrychowski

M.P.

, Sviderskiy

V.O.

, et al. (2014). Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell, 56, 360–375.

109.

Osellame

L.D.

, Singh

A.P.

, Stroud

D.A.

, Palmer

C.S.

, Stojanovski

, Ramachandran

, et al. (2016). Cooperative and independent roles of the Drp1 adaptors Mff, MiD49 and MiD51 in mitochondrial fission. J Cell Sci, 129, 2170–2181.

110.

Patten

D.A.

, Wong

, Khacho

, Soubannier

, Mailloux

R.J.

, Pilon-Larose

, et al. (2014). OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J, 33, 2676–2691.

111.

Peltier

, Goutman

S.A.

, and Callaghan

B.C.

(2014). Painful diabetic neuropathy. BMJ, 348, g1799.

112.

Perez

B.A.

, Shutterly

, Chan

Y.K.

, Byrne

B.J.

, and Corti

(2020). Management of neuroinflammatory responses to AAV-mediated gene therapies for neurodegenerative diseases. Brain Sci, 10, 119.

113.

Picci

, Wong

V.S.C.

, Costa

C.J.

, McKinnon

M.C.

, Goldberg

D.C.

, Swift

, et al. (2020). HDAC6 inhibition promotes alpha-tubulin acetylation and ameliorates CMT2A peripheral neuropathy in mice. Exp Neurol, 328, 113281.

114.

Pickles

, Vigie

, and Youle

R.J.

(2018). Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol, 28, R170–R185.

115.

Piguet

, Alves

, and Cartier

(2017). Clinical gene therapy for neurodegenerative diseases: past, present, and future. Hum Gene Ther, 28, 988–1003.

116.

Pizzo

, and Pozzan

(2007). Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol, 17, 511–517.

117.

Poole

A.C.

, Thomas

R.E.

, Andrews

L.A.

, McBride

H.M.

, Whitworth

A.J.

, and Pallanck

L.J.

(2008). The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A, 105, 1638–1643.

118.

Pulvers

J.N.

, and Marx

(2017). Factors associated with the development and severity of oxaliplatin-induced peripheral neuropathy: a systematic review. Asia Pac J Clin Oncol, 13, 345–355.

119.

, Yan

, Yu

, Guo

, Zhou

, Hu

, et al. (2016). Structures of human mitofusin 1 provide insight into mitochondrial tethering. J Cell Biol, 215, 621–629.

120.

Rappold

P.M.

, Cui

, Grima

J.C.

, Fan

R.Z.

, de Mesy-Bentley

K.L.

, Chen

, et al. (2014). Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo. Nat Commun, 5, 5244.

121.

Rasool

, and Trempe

J.-F.

(2018). New insights into the structure of PINK1 and the mechanism of ubiquitin phosphorylation. Crit Rev Biochem Mol Biol, 53, 515–534.

122.

Roberts

R.F.

, Tang

M.Y.

, Fon

E.A.

, and Durcan

T.M.

(2016). Defending the mitochondria: the pathways of mitophagy and mitochondrial-derived vesicles. Int J Biochem Cell Biol, 79, 427–436.

123.

Rocha

A.G.

, Franco

, Krezel

A.M.

, Rumsey

J.M.

, Alberti

J.M.

, Knight

W.C.

, et al. (2018). MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A. Science, 360, 336–341.

124.

Rojas-Charry

, Cookson

M.R.

, Nino

, Arboleda

, and Arboleda

(2014). Downregulation of Pink1 influences mitochondrial fusion-fission machinery and sensitizes to neurotoxins in dopaminergic cells. Neurotoxicology, 44, 140–148.

125.

Rubio

, Verrax

, Dewaele

, Verfaillie

, Johansen

, Piette

, et al. (2014). p38(MAPK)-regulated induction of p62 and NBR1 after photodynamic therapy promotes autophagic clearance of ubiquitin aggregates and reduces reactive oxygen species levels by supporting Nrf2-antioxidant signaling. Free Radic Biol Med, 67, 292–303.

126.

Rumora

A.E.

, Savelieff

M.G.

, Sakowski

S.A.

, and Feldman

E.L.

(2019). Disorders of mitochondrial dynamics in peripheral neuropathy: clues from hereditary neuropathy and diabetes. Int Rev Neurobiol, 145, 127–176.

127.

Runkel

E.D.

, Baumeister

, and Schulze

(2014). Mitochondrial stress: balancing friend and foe. Exp Gerontol, 56, 194–201.

128.

Ryan

M.T.

, and Stojanovski

(2012). Mitofusins ‘bridge’ the gap between oxidative stress and mitochondrial hyperfusion. EMBO Rep, 13, 870–871.

129.

Safiulina

, and Kaasik

(2013). Energetic and dynamic: how mitochondria meet neuronal energy demands. PLoS Biol, 11, e1001755.

130.

Sandoval

, Thiagarajan

, Dasgupta

S.K.

, Schumacher

, Prchal

J.T.

, Chen

, et al. (2008). Essential role for Nix in autophagic maturation of erythroid cells. Nature, 454, 232–235.

131.

Sauvé

, Lilov

, Seirafi

, Vranas

, Rasool

, Kozlov

, et al. (2015). A Ubl/ubiquitin switch in the activation of Parkin. EMBO J, 34, 2492–2505.

132.

Schmitt

, Grimm

, Dallmann

, Oettinghaus

, Restelli

L.M.

, Witzig

, et al. (2018). Circadian control of DRP1 activity regulates mitochondrial dynamics and bioenergetics. Cell Metab, 27, 657.e5–666.e5.

133.

Schofield

J.H.

, and Schafer

Z.T.

(2021). Mitochondrial reactive oxygen species and mitophagy: a complex and nuanced relationship. Antioxid Redox Signal, 34, 517–530.

134.

Schweers

R.L.

, Zhang

, Randall

M.S.

, Loyd

M.R.

, Li

, Dorsey

F.C.

, et al. (2007). NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci U S A, 104, 19500–19505.

135.

Seirafi

, Kozlov

, and Gehring

(2015). Parkin structure and function. FEBS J, 282, 2076–2088.

136.

Senft

, and Ronai

Z.A.

(2015). UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem Sci, 40, 141–148.

137.

Seretny

, Currie

G.L.

, Sena

E.S.

, Ramnarine

, Grant

, MacLeod

M.R.

, et al. (2014). Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain, 155, 2461–2470.

138.

Shen

, Cai

G.Q.

, Peng

J.P.

, and Chen

X.D.

(2015). Autophagy protects chondrocytes from glucocorticoids-induced apoptosis via ROS/Akt/FOXO3 signaling. Osteoarthritis Cartilage, 23, 2279–2287.

139.

Shetty

, Kumar

, and Bharati

(2019). Mito-TEMPO, a mitochondria-targeted antioxidant, prevents N-nitrosodiethylamine-induced hepatocarcinogenesis in mice. Free Radic Biol Med, 136, 76–86.

140.

Shi

, Lee

J.R.

, Grimes

D.A.

, Racacho

, Ye

, Yang

, et al. (2011). Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease. Hum Mol Genet, 20, 1966–1974.

141.

Shiba-Fukushima

, Arano

, Matsumoto

, Inoshita

, Yoshida

, Ishihama

, et al. (2014). Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet, 10, e1004861.

142.

Sifuentes-Franco

, Pacheco-Moisés

F.P.

, Rodríguez-Carrizalez

A.D.

, and Miranda-Díaz

A.G.

(2017). The role of oxidative stress, mitochondrial function, and autophagy in diabetic polyneuropathy. J Diabetes Res, 2017, 1673081.

143.

Sowter

H.M.

, Ratcliffe

P.J.

, Watson

, Greenberg

A.H.

, and Harris

A.L.

(2001). HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res, 61, 6669–6673.

144.

Starobova

, and Vetter

(2017). Pathophysiology of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci, 10, 174.

145.

Stavniichuk

, Shevalye

, Lupachyk

, Obrosov

, Groves

J.T.

, Obrosova

I.G.

, et al. (2014). Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy. Diabetes Metab Res Rev, 30, 669–678.

146.

Stojanovski

, Koutsopoulos

O.S.

, Okamoto

, and Ryan

M.T.

(2004). Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J Cell Sci, 117, 1201–1210.

147.

Thomas

K.J.

, McCoy

M.K.

, Blackinton

, Beilina

, van der Brug

, Sandebring

, et al. (2011). DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet, 20, 40–50.

148.

Tong

, Zablocki

, and Sadoshima

(2020). The role of Drp1 in mitophagy and cell death in the heart. J Mol Cell Cardiol, 142, 138–145.

149.

Tracy

, Dibling

B.C.

, Spike

B.T.

, Knabb

J.R.

, Schumacker

, and Macleod

K.F.

(2007). BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol, 27, 6229–6242.

150.

Trecarichi

, and Flatters

S.J.L.

(2019). Mitochondrial dysfunction in the pathogenesis of chemotherapy-induced peripheral neuropathy. Int Rev Neurobiol, 145, 83–126.

151.

Trempe

J.-F.

, Sauvé

, Grenier

, Seirafi

, Tang

M.Y.

, Ménade

, et al. (2013). Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science, 340, 1451–1455.

152.

Twig

, Elorza

, Molina

A.J.A.

, Mohamed

, Wikstrom

J.D.

, Walzer

, et al. (2008). Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J, 27, 433–446.

153.

Twig

, and Shirihai

O.S.

(2011). The interplay between mitochondrial dynamics and mitophagy. Antioxid Redox Signal, 14, 1939–1951.

154.

Ueda

, and Ishihara

(2018). Mitochondrial hyperfusion causes neuropathy in a fly model of CMT2A. EMBO Rep, 19, e46502.

155.

van der Bliek

A.M.

, Sedensky

M.M.

, and Morgan

P.G.

(2017). Cell biology of the mitochondrion. Genetics, 207, 843–871.

156.

van Vliet

A.R.

, Verfaillie

, and Agostinis

(2014). New functions of mitochondria associated membranes in cellular signaling. Biochim Biophys Acta, 1843, 2253–2262.

157.

Verdera

H.C.

, Kuranda

, and Mingozzi

(2020). AAV vector immunogenicity in humans: a long journey to successful gene transfer. Mol Ther, 28, 723–746.

158.

Wai

, and Langer

(2016). Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab, 27, 105–117.

159.

Wang

, Couture

, and Hong

(2014). Activated microglia in the spinal cord underlies diabetic neuropathic pain. Eur J Pharmacol, 728, 59–66.

160.

Wang

, Mishra

, Garbis

S.D.

, Moradian

, Sweredoski

M.J.

, and Chan

D.C.

(2021). Identification of new OPA1 cleavage site reveals that short isoforms regulate mitochondrial fusion. Mol Biol Cell, 32, 157–168.

161.

Wang

, Zhang

, Shen

, Kou

, Xie

, and Song

(2019). Activation of PINK1-Parkin-dependent mitophagy in Tri-ortho-cresyl phosphate-treated Neuro2a cells. Chem Biol Interact, 308, 70–79.

162.

Waseem

, Kaushik

, Tabassum

, and Parvez

(2018). Role of mitochondrial mechanism in chemotherapy-induced peripheral neuropathy. Curr Drug Metab, 19, 47–54.

163.

Wauer

, and Komander

(2013). Structure of the human Parkin ligase domain in an autoinhibited state. EMBO J, 32, 2099–2112.

164.

Whitley

B.N.

, Engelhart

E.A.

, and Hoppins

(2019). Mitochondrial dynamics and their potential as a therapeutic target. Mitochondrion, 49, 269–283.

165.

, Tian

, Hu

, Chen

, Huang

, Li

, et al. (2014). ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep, 15, 566–575.

166.

, Ocak

, Gao

, Tu

, Lenahan

C.J.

, Zhang

, et al. (2021). Selective autophagy as a therapeutic target for neurological diseases. Cell Mol Life Sci, 78, 1369–1392.

167.

Yamada

, Dawson

T.M.

, Yanagawa

, Iijima

, and Sesaki

(2019). SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy. Autophagy, 15, 2012–2018.

168.

Yamaguchi

, Murakawa

, Nishida

, and Otsu

(2016). Receptor-mediated mitophagy. J Mol Cell Cardiol, 95, 50–56.

169.

Yamashita

, Matsuoka

, Matsuda

, Kawai

, Sawa

, and Amaya

(2019). Dysregulation of p53 and Parkin induce mitochondrial dysfunction and leads to the diabetic neuropathic pain. Neuroscience, 416, 9–19.

170.

Yan

, Liu

X.H.

, Han

M.Z.

, Wang

Y.M.

, Sun

X.L.

, Yu

, et al. (2015). Blockage of GSK3beta-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer's disease. Neurobiol Aging, 36, 211–227.

171.

Yang

, Slone

, Li

, Lou

, Hu

Y.-C.

, Queme

L.F.

, et al. (2020). Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46^−/− mice. Hum Mol Genet, 29, 649–661.

172.

Yoon

, Krueger

E.W.

, Oswald

B.J.

, and McNiven

M.A.

(2003). The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol, 23, 5409–5420.

173.

Youle

R.J.

, and Karbowski

(2005). Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol, 6, 657–663.

174.

Youle

R.J.

, and Narendra

D.P.

(2011). Mechanisms of mitophagy. Nat Rev Mol Cell Biol, 12, 9–14.

175.

, Ma

, Li

, Wang

, and Wang

(2020a). Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics. Nat Commun, 11, 2549.

176.

, Nagasu

, Murakami

, Hoang

, Broderick

, Hoffman

H.M.

, et al. (2014). Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci U S A, 111, 15514–15519.

177.

, Lendahl

, Nistér

, and Zhao

(2020b). Regulation of mammalian mitochondrial dynamics: opportunities and challenges. Front Endocrinol (Lausanne), 11, 374.

178.

, Robotham

J.L.

, and Yoon

(2006). Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci U S A, 103, 2653–2658.

179.

Zaffagnini

, and Martens

(2016). Mechanisms of selective autophagy. J Mol Biol, 428, 1714–1724.

180.

Zhan

, Li

, Sun

, Dou

, Yang

, He

, et al. (2018). Effect of mito-TEMPO, a mitochondria-targeted antioxidant, in rats with neuropathic pain. Neuroreport, 29, 1275–1281.

181.

Zhang

, and Ney

P.A.

(2009a). Autophagy-dependent and -independent mechanisms of mitochondrial clearance during reticulocyte maturation. Autophagy, 5, 1064–1065.

182.

Zhang

, and Ney

P.A.

(2009b). Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ, 16, 939–946.

183.

Zhang

, Yuan

, Jiang

, Zhang

, Gao

, Shen

, et al. (2014). Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: involvement of PARK2-dependent mitophagy. Autophagy, 10, 1801–1813.

184.

Zhang

, Liu

, Li

, Zhu

, Xia

, et al. (2019). PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy protects PC12 cells against cisplatin-induced neurotoxicity. Med Sci Monit, 25, 8797–8806.

185.

Zhong

, Umemura

, Sanchez-Lopez

, Liang

, Shalapour

, Wong

, et al. (2016). NF-kappaB restricts inflammasome activation via elimination of damaged mitochondria. Cell, 164, 896–910.

186.

Zhou

, Carmona

, Muhammad

, Bell

, Landeros

, Vazquez

, et al. (2019). Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model. J Clin Invest, 129, 1756–1771.

187.

Zhu

, Massen

, Terenzio

, Lang

, Chen-Lindner

, Eils

, et al. (2013). Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis. J Biol Chem, 288, 1099–1113.