Mitophagy

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Mitochondrial dysfunction constitutes one of the hallmarks of aging and is characterized by irregular mitochondrial morphology, insufficient ATP production, accumulation of mitochondrial DNA mtDNA mutations, increased production of mitochondrial reactive oxygen species ROS and the consequent oxidative damage to nucleic acids, proteins and lipids. Mitophagy, a mitochondrial quality control mechanism enabling the degradation of damaged and superfluous mitochondria, prevents such detrimental effects and reinstates cellular homeostasis in response to stress. To date, there is increasing evidence that mitophagy is significantly impaired in several human pathologies including aging and age-related diseases such as neurodegenerative disorders, cardiovascular pathologies and cancer. Therapeutic interventions aiming at the induction of mitophagy may have the potency to ameliorate these dysfunctions. In this review, we summarize recent findings on mechanisms controlling mitophagy and its role in aging and the development of human pathologies. Mitochondria are highly organized and dynamic organelles that undergo continuous fission and fusion Chen and Chan, ; Pham et al. They originated from endosymbiotic proteobacteria and conferred substantial advantages for eukaryotic cells during evolution.

Mitophagy

Mitochondria are highly plastic and dynamic organelles that have graded responses to the changing cellular, environmental, and developmental cues. Mitochondria undergo constant mitochondrial fission and fusion, mitochondrial biogenesis, and mitophagy, which coordinately control mitochondrial morphology, quantity, quality, turnover, and inheritance. Mitophagy is a cellular process that selectively removes the aged and damaged mitochondria via the specific sequestration and engulfment of mitochondria for subsequent lysosomal degradation. It plays a pivotal role in reinstating cellular homeostasis in normal physiology and conditions of stress. Damaged mitochondria may either instigate innate immunity through the overproduction of ROS or the release of mtDNA, or trigger cell death through the release of cytochrome c and other apoptogenic factors when mitochondria damage is beyond repair. Distinct molecular machineries and signaling pathways are found to regulate these mitochondrial dynamics and behaviors. It is less clear how mitochondrial behaviors are coordinated at molecular levels. BCL2 family proteins interact within family members to regulate mitochondrial outer membrane permeabilization and apoptosis. They were also described as global regulators of mitochondrial homeostasis and mitochondrial fate through their interaction with distinct partners including Drp1, mitofusins, PGAM5, and even LC3 that involved mitochondrial dynamics and behaviors. In this review, we summarize recent findings on molecular pathways governing mitophagy and its coordination with other mitochondrial behaviors, which together determine cellular fate. Mitochondria are both the major source and the main targets of reactive oxygen species ROS. Under homeostatic conditions, mitochondrial ROS serve as retrograde signaling molecules for cell growth Diebold and Chandel, However, in conditions of stress or aging, mitochondrial ROS elicit oxidative damage to mitochondrial proteins, lipids, and DNA mtDNA , causing the malfunction of mitochondria. Dysfunctional mitochondria may produce even more ROS via vicious cycle that further amplify the release of ROS and mtDNA into the cytosol, which in turn can act as instigators of inflammation Nakahira et al. Non-reparable and severe damage of mitochondria leads to the release from the intermembrane space into the cytosol of cytochrome c and other pro-death factors Sinha et al.

SIRT3, a pivotal actor in mitochondrial functions: Metabolism, mitophagy, cell death and aging. McArthur, K. Ham S.

Federal government websites often end in. The site is secure. Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition.

Mitophagy is an evolutionarily conserved process involving the autophagic targeting and clearance of mitochondria destined for removal. Recent insights into the complex nature of the overlapping pathways regulating mitophagy illustrate mitophagy's essential role in maintaining the health of the mitochondrial network. In this review, we highlight recent studies that have changed the way mitophagy is understood, from initiation through lysosomal degradation. We outline the numerous mitophagic receptors and triggers, with a focus on basal and physiologically relevant cues, offering insight into why they lead to mitochondrial removal. We also explore how mitophagy maintains mitochondrial homeostasis at the organ and system levels and how a loss of mitophagy may play a role in a diverse group of diseases, including cardiovascular, metabolic, and neurodegenerative diseases. With disrupted mitophagy affecting such a wide array of physiological processes, a deeper understanding of how to modulate mitophagy could provide avenues for numerous therapies.

Mitophagy

Federal government websites often end in. The site is secure. Killackey et al. Mitophagy is an evolutionarily conserved process involving the autophagic targeting and clearance of mitochondria destined for removal. In this review, we highlight recent studies that have changed the way mitophagy is understood, from initiation through lysosomal degradation.

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Jessica Williams for the critical reading of our manuscript, and Dr. FEBS Lett. Eaten alive: a history of macroautophagy. Sekine S. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Tor and the Sin3-Rpd3 complex regulate expression of the mitophagy receptor protein Atg32 in yeast. Reports suggested that Drp1-mediated mitochondrial fission was dispensable for mitophagy Song et al. There is evidence that link alterations in the mitophagy with heart disease, highlighting that maintenance of an adequate mitochondrial clearance rate is crucial for cardiomyocyte viability. Nonselective autophagy of cytosolic enzymes by isolated rat hepatocytes. Even though the activation of NOX enzymes is responsible for the large production of ROS in advanced disease stages, mitochondrial damage is a relevant AS [ , ]. Selective and non-selective autophagic degradation of mitochondria in yeast. Cardioprotection and lifespan extension by the natural polyamine spermidine. Mitochondria and aging. Table 1 Aberrant mitophagy in neurodegenerative and neuropsychiatric diseases.

Degradation of mitochondria via a selective form of autophagy, named mitophagy, is a fundamental mechanism conserved from yeast to humans that regulates mitochondrial quality and quantity control.

Additionally, IL, an anti-inflammatory cytokine, induces mitophagy, preserves mitochondrial activity, and inhibits the glycolytic flux via mTOR inhibition in macrophages [ ]. Pros: This assay can assess a large number of cells compared with EM. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. Mitochondrion as a selective target for treatment of atherosclerosis: Role of mitochondrial DNA mutations and defective mitophagy in the pathogenesis of atherosclerosis and chronic inflammation. Fayet, G. Autophagy 4, — Drp1 is a cytosolic protein, but it can be recruited to the surface of mitochondria where it interacts with a partner protein, mitochondrial fission 1 Fis1 , through the adaptor proteins Mdv1 and Caf4 to trigger mitochondrial fission in yeast Griffin et al. It is also more objective and quantitative. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Thus, caution needs to be exercised when using these proteins as a marker for mitochondrial mass. Instead, there are many vesicular structures called membranous organelles MOs that are ubiquitinated and degraded together with the paternal mitochondria by autophagy Al Rawi et al. Palikaras K. Ebrahimi-Fakhari, D. Finally, increased numbers of depolarized mitochondria and mitophagy were observed in fibroblasts derived from patients deficient in coenzyme CoQ , a small lipophilic molecule critical for the transport of electrons from complexes I and II to complex III in the mitochondrial respiratory chain.