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.
Highlights
Mitochondria are organelles that govern energy transformation and ATP production through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS)
Mitophagy was suggested to play a protective role in stressinduced cell death and early studies showed that Parkin strongly inhibits the translocation of BCL2 associated X (BAX) to mitochondria, preventing apoptosis (Darios et al, 2003; Johnson et al, 2012)
BCL2 family proteins, and in particular BCL-xL, act as global regulators of mitochondrial homeostasis and quality control through their interaction with various partners including DRP1, mitosfusin 1 (MFN1)/2, and PGAM5, that are tightly controlled by reversible phosphorylation, acetylation, and ubiquitination, thereby modulating mitochondrial behaviors and cell fate
Summary
Mitochondria are organelles that govern energy transformation and ATP production through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS). 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, 2013) altogether triggering apoptosis, a specific form of programmed cell death This process is governed by the BCL2 protein family that integrates apoptotic signals and controls mitochondrial outer membrane permeabilization (MOMP). We recently have shown that PGAM5, a mitochondrial phosphatase, serves as a molecular switch for determining mitochondrial fate (apoptosis or mitophagy) by dephosphorylating BCL-xL, a key apoptosis inhibitor and FUNDC1, a mitophagy receptor These results demonstrated the integration of stress signals and the coordinated execution of graded responses in response to mitochondrial stress conditions (Ma K. et al, 2019). We provide a focused overview on the molecular mechanisms of mitophagy and its interplay with mitochondrial dynamics and behaviors, contributing to aging and aging-related diseases
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