Evidence strongly suggests that the global faltering of mitochondrial function throughout the body with advancing age has a lot to do with a decline in the effectiveness of mitophagy. Mitochondria are the power plants of the cell, a herd of hundreds swarming and replicating like bacteria in every cell to produce the chemical energy store molecule ATP. Mitophagy is the specialized form of autophagy that destroys worn and damaged mitochondria, recycling their component parts. Without it, cells would become overtaken by broken, malfunctioning mitochondria. Mitochondrial dysfunction leads to too little ATP, but also higher levels of harmful oxidative molecules that stress cells. In energy-hungry tissues such as muscle, the heart, the brain, loss of mitochondrial function is thought important in the progression of age-related conditions.

Mitophagy serves as a critical mechanism to eliminate damaged mitochondria and is regulated by multiple mechanistically distinct pathways. Cellular level studies have provided valuable insight into the signaling pathways regulating mitophagy, as well as mapping out how and when mitophagy occurs in a wide range of physiological and pathological conditions to counter cellular stressors such as reactive oxygen species or damaged mitochondria. A better understanding of mitochondrial turnover mechanisms, with an improved focus on how these pathways might contribute to disease pathogenesis, should allow for the development of more efficient strategies to battle numerous pathological conditions associated with mitochondrial dysfunction.

Mitophagy is an important element of overall mitochondrial quality control. Defective mitophagy is thought to contribute to normal aging as well as various neurodegenerative and cardiovascular diseases. In fact, aging by itself is a major risk factor for the pathophysiology of cardiovascular and neurodegenerative diseases. Increasing evidence suggests that mitophagy failure accelerates aging. Interestingly, a marked age-dependent decline in mitophagy has been observed in the hippocampus of the mouse brain, an area where new memory and learning are encoded. This strengthens the hypothesis that mitophagy might regulate neuronal homeostasis and that a decline in mitophagy might predispose to age-dependent neurodegeneration. Age-related mitochondrial function deterioration is underlined as a key feature of other diseases, such as obesity, diabetes, and cancer. Therefore, maintaining a healthy mitochondrial network via functional mitophagy may serve as an attractive therapeutic strategy in the treatment of a wide range of age-related diseases, and potentially regulate longevity.

The emergence of nutritional and pharmacological interventions to modulate autophagy/mitophagy and to serve as a potential therapeutic model is quite encouraging. Accumulation of ubiquitinated outer mitochondrial membrane proteins has been proposed to act as a signal for selective mitophagy. Ubiquitination of mitochondrial proteins is positively regulated, in part, by the E3 ubiquitin ligase, Parkin. In contrast, removal of ubiquitin is achieved by the action of resident mitochondrial deubiquitinases, most notably USP30, thereby acting to antagonize mitophagy. Inhibition of USP30 enzyme activity may provide an unambiguous avenue to pursue the role of mitophagy as a therapeutic target.

Recently, three promising candidates that may stimulate and reinvigorate mitophagy process have been demonstrated to reduce the accumulation of amyloid-beta and phosphorylated tau in Alzheimer’s mouse brains. These compounds, including nicotinamide mononucleotide, urolithin A, and actinonin, can improve symptoms of AD and dementia symptoms in preclinical models. In addition, TatBeclin 1 peptide, derived from a region of the autophagy protein, beclin 1, can promote autophagy/mitophagy and improve mitochondrial function in heart failure animal models. Therefore, identifying more efficient and specific agents that can modulate the clearance of defective mitochondria are likely to have significant therapeutic benefits.

Link: https://doi.org/10.3389/fcell.2020.00294