Mitophagy, Mitochondrial Homeostasis, and Cell Fate

Abstract

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.

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

“…ROS bursts are a major pro-inflammatory stimulus per se via activation of nuclear factor κB (NF-κB) [47]. However, mitochondrial ROS also participate in other cellular processes including the activation of mitochondrial permeability transition pore (mPTP), dysregulation of mitophagy, imbalances in mitochondrial dynamics, and programmed cell death [48]. These processes represent potential routes for mtDNA displacement following ROS burst as evidenced by the finding of oxidized mtDNA fragments outside of mitochondria in the setting of several metabolic diseases [43,[49][50][51][52][53] (Figure 1).…”

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

“…However, in post-mitotic cells, a function of fission is to separate dysfunctional segments of the mitochondria from the normal ones. The separated dysfunctional segments enter an autophagic process known as mitophagy [ 121 ]. This implies that fission is to some degree associated with mitochondrial injury in post-mitotic cells.…”

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

“…For most LSDs, the integrity of the lysosomal membrane is compromised by the storage material load due to dysfunctional lysosomal hydrolases. The lysosomal membrane becomes mechanically damaged as a result and causes lysosomal membrane permeability (LMP) [126][127][128]. Since the lysosome is home to many catabolic proteins, LMP may cause the release of proteases into the cytosol, which can initiate a complex pathway resulting in mitochondrial permeabilization.…”