Mitophagy is an evolutionarily conserved cellular process to remove dysfunctional or superfluous mitochondria, thus fine-tuning mitochondrial number and preserving energy metabolism. In this Review, we survey recent advances towards elucidating the molecular mechanisms that mediate mitochondrial elimination and the signalling pathways that govern mitophagy. We consider the contributions of mitophagy in physiological and pathological contexts and discuss emerging findings, highlighting the potential value of mitophagy modulation in therapeutic intervention.

Mitochondria are cellular organelles essential for multiple biological processes, including energy production, metabolites biosynthesis, cell death, and immunological responses among others. Recent advances in the field of immunology research reveal the pivotal role of energy metabolism in innate immune cells fate and function. Therefore, the maintenance of mitochondrial network integrity and activity is a prerequisite for immune system homeostasis. Mitochondrial selective autophagy, known as mitophagy, surveils mitochondrial population eliminating superfluous and/or impaired organelles and mediating cellular survival and viability in response to injury/trauma and infection. Defective removal of damaged mitochondria leads to hyperactivation of inflammatory signaling pathways and subsequently to chronic systemic inflammation and development of inflammatory diseases. Here, we review the molecular mechanisms of mitophagy and highlight its critical role in the innate immune system homeostasis.

Aging is a complex biological process affecting almost all living organisms. Although its detrimental effects on animals' physiology have been extensively documented, several aspects of the biology of aging are insufficiently understood. Mitochondria, the central energy producers of the cell, play vital roles in a wide range of cellular processes, including regulation of bioenergetics, calcium signaling, metabolic responses, and cell death, among others. Thus, proper mitochondrial function is a prerequisite for the maintenance of cellular and organismal homeostasis. Several mitochondrial quality control mechanisms have evolved to allow adaptation to different metabolic conditions, thereby preserving cellular homeostasis and survival. A tight coordination between mitochondrial biogenesis and mitochondrial selective autophagy, known as mitophagy, is a common characteristic of healthy biological systems. The balanced interplay between these two opposing cellular processes dictates stress resistance, healthspan, and lifespan extension. Mitochondrial biogenesis and mitophagy efficiency decline with age, leading to progressive accumulation of damaged and/or unwanted mitochondria, deterioration of cellular function, and ultimately death. Several regulatory factors that contribute to energy homeostasis have been implicated in the development and progression of many pathological conditions, such as neurodegenerative, metabolic, and cardiovascular disorders, among others. Therefore, mitophagy modulation may serve as a novel potential therapeutic approach to tackle age-associated pathologies. Here, we review the molecular signaling pathways that regulate and coordinate mitophagy with mitochondrial biogenesis, highlighting critical factors that hold promise for the development of pharmacological interventions toward enhancing human health and quality of life throughout aging.