Mitochondrial Translocation in Young and Old Cells

Introduction

T he interior of the cell is very crowded, excluding a large part of the volume that is available to colloids and organelles. ¹ The small volume available seems to decrease further with aging. ^2,3 How the mitochondria are able to translocate in this milieu is enigmatic. Mitochondria are very flexible, easily changing form, dividing and reuniting, preferentially moving in rows along microtubule chains. ^4,5 A model has been described in which the mitochondrion is translocated by motor proteins (kinesins and dyneins) tethered to the microtubule, stopping at a location low in adenosine triphosphate (ATP) with a Ca²⁺-mediated disruption of the tether. ⁶ Other mechanisms may be involved. For example, a possible mechanism for the translocation of a mitochondrion detached from the microtubule could be for it to follow fluid movements within the cell.

Hypothesis

The mitochondrion absorbs (by specific transport mechanisms) pyruvic acid (the end product of anerobic glycolysis), phosphate ions, adensoine diphosphate (ADP), fatty acids from lipid droplets, and (by diffusion) O₂ from the cytosol, and returns ATP and CO₂. Due to the decrease in pyruvate and phosphate ions, the osmotic pressure around the mitochondrion decreases; the exchanges ADP–ATP and O₂–CO₂, and removal of lipid droplets, are assumed to have a negligible impact on the osmotic pressure. This implies that the osmotic pressure is higher in neighboring locations of the cytosol, with higher amounts of pyruvate and phosphate. To level out these differences in osmotic pressure, there is a transfer of water (there is also an opposite diffusion of the ions, which is assumed to be slower). Mitochondria (and also lipid droplets) are assumed to be directed by such fluid movements, which are most rapid through the largest holes, through which it may be possible for a mitochondrion to pass. In this way, the mitochondria may find a location in the cytosol that is rich in nutrition (pyruvate, lipid droplets). In senescent cells, the translocation of the mitochondria is assumed to be hampered by accumulated cross-linked protein.

Discussion

A prerequisite for the proposed mitochondrial translocation by fluid movement is that the difference in osmotic pressure due to differences in pyruvate and phosphate ion concentration is high enough to create the water movement, which remains to be shown (intracellular HPO₄ ²⁻ concentration about 5 × 10⁻² M). However, if several mitochondria cooperate, the concentration may be lowered in a comparatively large volume, which should give rise to a significant intracellular water movement.

To follow the fluid movements, the mitochondrion is assumed to be detached from the microtubule, due to a high Ca²⁺ concentration (about 5 × 10⁻⁶ M). ^4,6 When the ATP concentration next to the mitochondrion increases after some delay, the endoplasmic reticulum membrane and the cell membrane remove Ca²⁺ from the cytosol, and after some further delay the concentration of Ca²⁺ becomes low enough for the mitochondrion to become tethered to the microtubule. ⁶ Before that happens, most mitochondria are assumed to have escaped to a neighboring location with a higher osmotic pressure that is rich in Ca²⁺ and nutrition and low in ATP. An increase in hydrostatic pressure at the end of the osmotic fluid movement may persist, ⁷ which may reinforce the fluid movement. In addition, a mitochondrion may push an obstructing chain aside to facilitate the movement.

A belated mitochondrion may become trapped in a location high in ATP and low in Ca²⁺, thus being tethered to a microtubule. ⁶ In this case, it is moved either by a kinesin to the plus end of the microtubule, or to the minus end by a dynein, to a location high in Ca²⁺(and low in ATP, high in nutrition), where it is detached. ⁶ Also, lipid droplets may move tethered to microtubule chains, ⁸ but here they are assumed to move detached with fluid movement.

In an unpublished analysis of the translocation of a globular colloid in a polymer solution, it was found that the volume available for translocation is the volume available at equilibrium plus an additional volume due to the colloid moving along the polymer chain. This additional volume may be reconciled with and explain the mitochondrial translocating preferentially along the microtubule chains.

In this context, it is interesting to consider the bacterium Shigella, which easily invades a cell and travels freely in the cytoplasm with a myosin-based flagella, whereas the mobility of a mutant strain of Shigella with a knocked-out microtubule-specific protease is severely hampered. ⁹ This implies that in a young cell the mobility-obstructing effect is exhibited predominantly by the microtubule polymer; it is known that polymers are more efficient than globular components at excluding large colloids and organelles from part of the water volume. In old cells, the available volume is assumed to be further decreased by the exclusion effect of cross-linked protein chains. ^2,3

In striated muscle, the mitochondria are fixed. ⁴ Transport of water here does not seem possible, and another mechanism for mitochondrial function has to be considered. Although inefficient when the distances are long, diffusion is very rapid over short distances. The exchange of pyruvate, phosphate, and other metabolites (e.g., lipid droplet fatty acids linked to carnitine) may be assumed to be rapid in the muscle with mitochondria close to the myofibrils, presumably more rapid than by the mechanism described above with mitochondria translocating for longer distances.

In conclusion, osmosis-induced fluid movements directing the mitochondria to locations in the cytosol that is rich in nutrition may contribute to the high mobility of mitochondria in young cells. In senescent cells, the translocation may be obstructed by cross-linked proteins. With mitochondria fixed, as in striated muscle, the metabolic exchange may be governed by diffusion of the metabolites.