Mechanism and role of mitophagy in the development of severe infection

Abstract

Mitochondria produce adenosine triphosphate and potentially contribute to proinflammatory responses and cell death. Mitophagy, as a conservative phenomenon, scavenges waste mitochondria and their components in the cell. Recent studies suggest that severe infections develop alongside mitochondrial dysfunction and mitophagy abnormalities. Restoring mitophagy protects against excessive inflammation and multiple organ failure in sepsis. Here, we review the normal mitophagy process, its interaction with invading microorganisms and the immune system, and summarize the mechanism of mitophagy dysfunction during severe infection. We highlight critical role of normal mitophagy in preventing severe infection.

Fig. 1. Mechanism of macromitophagy.

After cells suffer endogenous and exogenous stimulators, mitophagy is initiated to clear injured mitochondria by recruiting PINK1-Parkin to ubiquitinate mitochondria. The ULK1 complex and PI3KC3 complex I synthesize robust PI3P at the omegasome. Autophagy adapters or receptors bind ATG8 to anchor mitochondria to the phagophore. The double membrane of the phagophore lengthens and enwraps mitochondria. Mitophagosomes fuse with lysosomes mediated by the tethering proteins (such as HOPS complex and PLEKHM1) and SNAREs. Finally, lysosomal enzymes degrade the inner membrane and contents of the mitophagosome. Various microorganisms, such as CVB3, IAV, Legionella, HPIV3, SARS-CoV-2, and Hantavirus, disturb the process of mitophagy, resulting in mitochondria injury and autophagosome accumulation. ATG autophagy-related, COP-II coat protein complex-II, CVB3 coxsackievirus B3, ER endoplasmic reticulum, HOPS homotypic fusion and protein sorting, HPIV3 human parainfluenza virus 3, IAV influenza A virus, LPS lipopolysaccharides, PI3P phosphatidylinositol-3-phosphate, PINK1 PTEN-induced putative kinase 1, PLEKHM1 pleckstrin homology domain-containing protein family member 1, RAB7A RAS oncogene family 7A, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, SNARE soluble N-ethylmaleimide-sensitive factor attachment protein receptor, TBK1 TANK binding kinase 1, TLR toll-like receptor, ULK1 unc-51 like autophagy activating kinase 1, WIPI WD repeat domain phosphoinositide interacting.

Fig. 2. Mitophagy interacts with the inflammatory cascade.

A Mitochondria contribute to MAVS-induced anti-infective response. mtDNA promotes interferon expression by cGAS-STING pathway. HPIV3, SARS-CoV2 and Hantavirus inhibit the role of MAVS to survive themselves. B DAMPs derived from mitochondria induce apoptosis and pyroptosis in host cells by activating caspase 1/3/7. Mitophagy blocks inflammatory pathway via scavenging mitochondria-derived DAMPs. TLR-NF-κB signaling promotes p62-dependent mitophagy to inhibit mitochondria-dependent inflammation and cell death. TLRs also activate RIP1-RIP3 signaling to induce incomplete mitophagy and necroptosis. cGAS-STING cyclic guanosine monophosphate–adenosine monophosphate synthase and stimulator of IFN genes. IRF interferon regulatory factor, MAVS mitochondrial antiviral signaling protein, mtDNA mitochondrial DNA, dsDNA: double strand DNA, Cyt c Cytochrome c, DAMPs danger-associated molecular patterns, RIP receptor interacting protein.

Fig. 3. The roles of mitophagy at the tissue and organ levels.

Mitophagy inhibits organ dysfunctions, including brain, lung, heart, liver and muscle weakness, and modulates immune cell differentiation. AT2 alveolar type 2, AMPK AMP-activated protein kinase, mTOR mechanistic target of rapamycin.

Fig. 4. A summary of relations between mitophagy, mitochondria, and severe infection.

Mitophagy and mitochondria cooperate in regulating inflammation, apoptosis, and necroptosis in the cells and extracellular vesicles. Both of them participate in regulating multiple pathophysiological processes in severe infection, such as organ functions, platelet and immune cell functions, and eliminating pathogens.