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.

Keywords: cell fate; mitochondrial apoptosis; mitochondrial dynamics; mitophagy; mitophagy receptors.

FIGURE 1

The phosphatase PGAM5 regulates mitochondrial fate. The phosphatase PGAM5 is a dimeric protein that can bind with and dephosphorylate BCL-xL at Ser62, which increases its antiapoptotic function and thus inhibits apoptotic cell death. Mitochondrial oxidative stress causes the transformation of dimeric PGAM5 into a multimeric state that fails to bind with BCL-xL, but instead interacts with and dephosphorylates FUNDC1 at Ser13 to mediate mitochondrial fission and mitophagy. The dephosphorylation of FUNDC1 cooperates with the phosphorylation of BCL-xL, aggravating cell death when mitophagy is blocked.

FIGURE 2

Mitochondrial homeostasis and cell fate. Mitochondria are dynamic organelles that constantly divide and fuse in healthy cells and mitochondrial biogenesis and mitophagy cooperate to maintain mitochondrial quality. Mitochondrial fission usually is a prerequisite for ubiquitin- and receptor-mediated mitophagy facilitating the removal of aged and damaged mitochondria. Severe stress-induced mitochondrial damage can lead to mitochondria outer membrane permeabilization (MOMP) that in turn triggers apoptosis. The clearance of depolarized mitochondria by mitophagy (before MOMP occurs) mitigates this process. Besides, mitophagy reduces the production of mtROS and the cytosolic secretion of mtDNA, which further prevents excess immune response.