A Commentary on Mitophagy

Mitophagy is the process of selecting and breaking down worn mitochondria. There are hundreds of mitochondria in every cell, and regular removal of damaged mitochondrial followed by replacement through replication of viable mitochondria is needed in order to prevent harm to cell functions. Unfortunately, mitophagy appears to become less effective with age, for a variety of reasons, including changes in mitochondrial dynamics, and failures in broader autophagic processes responsible for moving mitochondria to a lysosome for enzymatic deconstruction. Numerous research groups aim to produce small molecule drugs or supplements capable of improving mitochondrial function in later life by improving the operation of mitophagy, and a range of approaches exist that appear to produce incremental benefits, such as mitoQ and urolithin A. As of yet, producing a greater positive impact than that resulting from exercise has proven to be a challenge, however.

The principal process by which overall mitochondrial quality is maintained is through selective culling of dysfunctional and damaged organelles by mitochondrial autophagy, or mitophagy. It is posited that age-related deterioration in mitophagy, and the consequent interruption of mitochondrial quality control, can contribute to adverse aging phenotypes partly because of increased elaboration of mitochondria-derived ROS from improperly retained damaged organelles. A corollary to this hypothesis is that improving the overall fitness of the cellular mitochondrial collective by forced mitophagy activation might delay age-related cell degeneration and ameliorate age-associated diseases. Experimental systems using overexpression of mitophagy and related factors support this proposition.

Mitochondrial quality control is the canonical role for mitophagy, and likely the mechanism by which its enhancement prevents premature senescence. However, culling defective mitochondria is not the sole purpose of mitophagy, nor is the PINK-Parkin pathway the only pathway to mitophagy. Accumulating evidence in mammalian systems suggests that Parkin-mediated mitophagy may be more important as a stress-induced or developmentally regulated mechanism, and that other paths comprise the major mechanism for homeostatic quality control through "maintenance mitophagy". Moreover, Parkin-mediated mitophagy can play an essential role during cell-wide mitochondrial replacement, generally accelerating mitochondrial turnover for either quantity control (i.e., removing excess mitochondria) or provoking a metabolic adaptation in response to an altered environmental context (as in converting the mitochondrial collective from lipid- to carbohydrate-based metabolism and vice versa).

Mitochondrial abnormalities such as fragmentation, loss of inner membrane polarization and increased ROS production have been widely reported in both chronically progressive neurodegenerative diseases and genetic neurological syndromes manifesting an age-dependent phenotype. There is growing interest in developing approaches to correct secondary mitochondrial abnormalities as one component of an ensemble therapy approach to these incurable and largely untreatable diseases. One promising approach attacks the problem of mitochondrial fragmentation, either by inhibiting mitochondrial fission or stimulating mitochondrial fusion. It is intriguing to speculate that these tactics might act synergistically with pharmaceutical activation of mitophagy to correct mitochondrial abnormalities in neurodegenerative diseases.

Link: https://doi.org/10.20517/jca.2022.36

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