Mitochondria are bacterial-like cell components, hundreds of them in each cell working to create the adenosine triphosphate (ATP) energy store molecule used to power cellular processes. Mitochondria are dynamic structures, and constantly fuse together, split apart, and replicate like bacteria. Worn mitochondria are removed on a regular basis by the cellular quality control mechanism of mitophagy, a specialized form of autophagy. The survivors replicate to make up the losses.
With advancing age, mitochondrial dynamics shift to favor fusion over fission, producing larger structures that are resilient to mitophagy. The processes of mitophagy (and autophagy in general) are also thought to decline in efficiency for other reasons. This leads to the accumulation of malfunctioning, worn, broken mitochondria in cells throughout the body, and a consequent loss of cell function and tissue function. This is most likely an important component of degenerative aging, and thus restoration of mitophagy and mitochondrial function are important goals in the field of rejuvenation research.
Mitochondria are important for cellular life and death, implying that mitochondrial homeostasis must be tightly controlled and fine-tuned when cells respond to stress. Mitophagy is the primordial mechanisms for mitochondrial quality and quantity control and multiple mechanisms control this process. Some studies indicate an ample crosstalk between different mitophagy pathways that may coordinate and complement to deal with environmental challenges.
Exercise has long been known to promote healthy aging and decrease the susceptibility to age-related diseases probably, depending on the induction of autophagy. Mitophagy may also be involved in the beneficial effects of exercise. A recent study has shown that exercise activates the AMPK-ULK1 cascade to provoke the removal of damaged mitochondria via mitophagy. Caloric restriction is yet another way to extend healthy lifespan. Similar to exercise, nutrient deprivation activates the AMPK-ULK1 cascade that is required for mitophagy to remove damaged mitochondria and promote cellular survival.
Some compounds exert their lifespan extending effect via mitophagy. Thus, urolithin A extends lifespan and improves fitness during C. elegans aging and improves muscle function and exercise capacity in rodents. In-depth analysis demonstrates that mitophagy is required for the beneficial effect of urolithin A. Nicotinamide adenine dinucleotide (NAD) levels decrease with age, while the upregulation or replenishment of NAD metabolism has been shown to exhibit beneficial effects against aging and age-associated diseases. Treatments that increase intracellular NAD+ improve mitochondrial quality via mitophagy. Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), prolongs life in yeast, worms, flies, and mice. Recent studies indicate that eliminating damaged mitochondria via mitophagy may be one of the mechanisms responsible for the beneficial effects of rapamycin.
In conclusion, dysfunction of mitochondria is one of the major characteristics of aging and age-related disease. Increasing evidence shows that mitophagy (by removing damaged mitochondria) is significantly involved in counterbalancing age-related pathological conditions. Thus, chronic stimulation of mitochondrial turnover by enhancing mitophagy is a promising approach to delay age-related diseases and to extend healthspan and lifespan.