Mitochondrial transfer is highly significant under physiological as well as pathological states given the emerging recognition of mitochondria as cellular “processors” akin to microchip processors that control the operation of a mobile device. Mitochondria play indispensable roles in healthy functioning of the brain, the organ with the highest energy demand in the human body and therefore, loss of mitochondrial function plays a causal role in multiple brain diseases. In this review, we will discuss various aspects of extracellular vesicle (EV)-mediated mitochondrial transfer and their effects in increasing recipient cell/tissue bioenergetics with a focus on these processes in brain cells. A subset of EVs with particle diameters >200 nm, referred to as medium-to-large EVs (m/lEVs), are known to entrap mitochondria during EV biogenesis. The entrapped mitochondria are likely a combination of either polarized, depolarized mitochondria or a mixture of both. We will also discuss engineering approaches to control the quality and quantity of mitochondria entrapped in the m/lEVs. Controlling mitochondrial quality can allow for optimizing/maximizing the therapeutic potential of m/lEV mitochondria—a novel drug with immense potential to treat a wide range of disorders associated with mitochondrial dysfunction.
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