A small but significant number of cells become overtaken by damaged, dysfunctional mitochondria over a lifetime, and this process is one of the contributing causes of degenerative aging. Mitochondria are important to many cellular processes, and quality control mechanisms aim to either repair damage or remove and replace damaged mitochondria. Mitochondrial theories of aging postulate ways in which some forms of damage subvert quality control, allowing dysfunctional mitochondria to preferentially avoid recycling, leading to the end result described above.
This review paper looks at what is known of natural mitochondrial quality control mechanisms:
Repairing or disposing of a malfunctioning object is an everyday dilemma. Replacing an item may be quicker than repairing it, but may also be more costly. Cells are faced with the same options when their organelles are challenged. Ensuring the health of the mitochondrial network is of utmost importance for cellular health and, not surprisingly, mitochondrial quality control can take both the repair and disposal routes. Spectacular advances have been made in recent years and a picture is starting to emerge of what drives a cell to take one or the other path. Interestingly, mitochondrial quality control seems to be deficient in various medically relevant conditions, such as neurodegeneration and aging.
Since the original observations that calorie restriction could extend lifespan, a close connection exists between energy metabolism and aging. Mitochondria, as an important source of reactive oxygen species, have long been considered a prime suspect for causing cellular aging. However, a different picture emerges from recent studies. In a screen for long-lived worm mutants, Andrew Dillin's lab found that creating imbalance in the assembly of respiratory chain subunits caused increased lifespan. That phenomenon was soon related to an activation of the mitochondrial unfolded protein response (UPR). Indeed, this increase in lifespan did not correlate to a reduced activity of the mitochondria, but to an activation of mitochondrial UPR, since increase in lifespan is blunted in mutants incapable of mounting a mitochondrial UPR. Thus, although direct causality between mitochondrial UPR induction and lifespan extension is not clearly established, it seems that mitochondrial quality control, more than mitochondrial activity, contributes to aging regulation. These observations, originally made in worms, could be extended to mice, where a large-scale genomic association study found that longevity was associated with variations in genes encoding mitochondrial proteins.