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Mitophagy is the selective version of autophagy focused on recycling mitochondria. Every cell contains hundreds of mitochondria, their primary responsibility the generation of chemical energy store molecules to power cellular processes. Mitochondria are the descendants of ancient symbiotic bacteria. They lead dynamic lives, replicating like bacteria, passing component parts around, and fusing together. Mitophagy is a quality control mechanism, removing damaged mitochondria in order to prevent cellular dysfunction. A good deal of evidence suggests that age-related declines in mitochondrial function are in large part caused by a progressive failure of the operation of mitophagy.
Like the general processes of autophagy, mitophagy is thought to decline in efficiency with age. This can result from reasons peculiar to the involvement of mitochondria, such as changes in their dynamics that lead to greater resistance to mitophagy, or to defects in the common mechanisms of autophagy, such as formation or transport of autophagosomes, or defects in the function of the lysosomes responsible for breaking down cellular waste. It isn’t always completely clear that specific metrics of autophagy are relevant in every tissue, or that autophagy is declines with age in all tissues, however. Too much autophagy can cause as much harm as too little autophagy, but a raised level of a specific autophagy-associated protein might in fact indicate a breakage in later portions of the autophagic process, rather than greater autophagy per se. Other ambiguities attend the various means of assessing autophagy. It is an area of research that still requires considerable work aimed at improving fundamental understanding.
Mitophagy in the aging nervous system
Living longer is changing our global population, with major ramifications for brain health and cognition. Why some humans experience accelerated neural aging compared to others remains to be fully understood. Autophagy and mitophagy are pathways of outstanding clinical interest with major relevance for neural integrity because human neural function depends upon quality control over a timespan of decades. Although mitophagy levels decline in short-lived model organisms, it remains unclear if decreased levels of mitophagy are a hallmark of all cell types during natural aging in the mammalian nervous system. Furthermore, it remains unclear if certain cerebral regions and cellular subtypes exhibit greater susceptibility to age-related changes than others. For example, cortical thickness is a widely used metric in human aging studies but the first large-scale heterochronic datasets (brain charts) are only beginning to emerge. Delineating the regional and cell subset-specific regulation of mitophagy will be critical to develop neuroprotective interventions that might improve healthspan or even reverse human age-related degeneration.
It will also be exciting to discover the possible interplay between emerging mitophagy pathways, and age-dependent pathology in the mammalian nervous system. Crosstalk between basal mitophagy and other mitochondrial responses e.g., outer membrane remodeling in response to infection and signalling or degradative mitochondria-derived vesicle (MDV) formation also represent intriguing avenues for future investigation. Whether elevated levels of mitophagy are beneficial for neural integrity also remains a mystery. What is the “minimum effective threshold” of basal mitophagy or macroautophagy required to safeguard neural integrity? How can we control or fine tune mitophagy to prevent a deleterious outcome? What is the relationship between physiological mitophagy and contemporary concepts in geroscience, such as epigenetic aging? The continued development and characterisation of novel tools presents a unique opportunity to resolve these longstanding questions.
What is the role of selective autophagy in the neuroprotective effects afforded by behavioral interventions? There are clear pro-longevity effects of exercise for cognitive, cerebrovascular, and systemic health. Indeed, autophagy and mitophagy are impacted by exercise in different model systems. Developing robust protocols and pharmacological strategies to augment selective autophagy pathways in humans represents a major challenge, because we do not have rapid, non-invasive assays that can reliably monitor distinct forms of autophagy in the clinic (at point of care). Equally, such clinical assays would need to distinguish between the degradative and signalling functions of autophagy (not a trivial task, even under laboratory conditions). Moreover, it remains unknown if changes in serum levels of autophagy markers reflect alterations in cell or tissue-specific autophagy pathways. These are challenging questions, but also exciting opportunities that will lead to a better understanding of physiological mitophagy in tissue development, disease and repair.