Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance

Abstract

The maintenance of a healthy and functional mitochondrial network is critical during development as well as throughout life in the response to physiological adaptations and stress conditions. Owing to their role in energy production, mitochondria are exposed to high levels of reactive oxygen species, making them particularly vulnerable to mitochondrial DNA mutations and protein misfolding. Given that mitochondria are formed from proteins encoded by both nuclear and mitochondrial genomes, an additional layer of complexity is inherent in the coordination of protein synthesis and the mitochondrial import of nuclear-encoded proteins. For these reasons, mitochondria have evolved multiple systems of quality control to ensure that the requisite number of functional mitochondria are present to meet the demands of the cell. These pathways work to eliminate damaged mitochondrial proteins or parts of the mitochondrial network by mitophagy and renew components by adding protein and lipids through biogenesis, collectively resulting in mitochondrial turnover. Mitochondrial quality control mechanisms are multi-tiered, operating at the protein, organelle and cell levels. Herein, we discuss mitophagy in different physiological contexts and then relate it to other quality control pathways, including the unfolded protein response, shedding of vesicles, proteolysis, and degradation by the ubiquitin-proteasome system. Understanding how these pathways contribute to the maintenance of mitochondrial homeostasis could provide insights into the development of targeted treatments when these systems fail in disease.

Toward understanding genomic instability, mitochondrial dysfunction and aging

“…This is consistent with the fact that several age‐related diseases are characterized by loss of energy homeostasis and mitochondrial dysfunction . The health of the mitochondrial pool is maintained by fission and fusion of individual mitochondria and autophagic removal of damaged mitochondria by mitophagy . High cellular energy demand stimulates mitochondrial fusion and formation of mitochondrial networks .…”

BRCA1 Deficiency Impairs Mitophagy and Promotes Inflammasome Activation and Mammary Tumor Metastasis

“…Mitophagy is a specialized autophagy for clearing damaged mitochondria, and plays a critical role in maintaining mitochondrial functions. A major trigger for mitophagy is via the PTEN‐induced putative kinase 1 (PINK1)/Parkin pathway 9. To verify the effect of BRCA1 on mitophagy, we first monitored occurrence of mitophagy in Hela cells that express mCherry‐Parkin (Hela‐mCherryParkin cells) with mitochondrial damage treatment in different ways.…”

“…Mitochondria are crucial organelles for energy production and cellular homeostasis in mammalian cells; therefore, the maintenance of a healthy mitochondrial network is critical in the development as well as in the response to physiological adaptations and stress conditions throughout life 9. Mitophagy, a selective autophagic process, plays an important role in maintaining mitochondrial function.…”

Lipopolysaccharide‐induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo

“…Mitochondria, which play a central role in energy metabolism, are dynamic organelles that undergo biogenesis, fission, fusion, and mitophagy (autophagic degradation). The balance of these processes allows the reorganization of mitochondrial components and the elimination of damaged material, thereby maintaining a healthy mitochondrial population (Pickles, Vigie, & Youle, ; Wai & Langer, ). Recent studies have linked mitochondrial dynamics to energy demand, suggesting changes in mitochondrial architecture as a mechanism for bioenergetic adaptation to inflammation (Nasrallah & Horvath, ).…”