Megamitochondria and a proposed model of mitochondrial dynamics in regulating cell death, pyrimidine metabolism and mtDNA-mediated cGAS–STING innate immune responses in ALD and liver tumourigenesis. (IMAGE)

First Hospital of Jilin University

Megamitochondria and a proposed model of mitochondrial dynamics in regulating cell death, pyrimidine metabolism and mtDNA-mediated cGAS–STING innate immune responses in ALD and liver tumourigenesis.

Caption

(A) Representative H&E staining of human alcohol-associated hepatitis liver and (B) electron microscopy images from a Gao-binge alcohol-fed mouse liver (see Ma et al3). Arrows indicate megamitochondria. Scale bars: 100 µm in (A) and 500 nm in (B). (C) Alcohol consumption reduces hepatic DRP1 levels, leading to decreased mitochondrial fission and the formation of megamitochondria. The lower-left grey module in (C) illustrates mitochondrial stasis during chronic alcohol exposure: the curved arrows denote the normal cycling between DRP1-mediated fission and MFN1/MFN2-mediated fusion, whereas reductions in both processes suppress mitochondrial dynamic remodeling. Newly formed megamitochondria show increased oxygen consumption, NAD+ production and fatty acid beta-oxidation to protect against ALD; however, chronic megamitochondria lose these protective responses, resulting in increased release of mitochondrial apoptotic factors and mtDNA. This causes heightened apoptosis and a cGAS–STING-mediated inflammatory response. Megamitochondria also demonstrate increased pyrimidine synthesis, which3 may promote cell proliferation alongside increased cell death and innate immune responses, ultimately contributing to liver injury and liver tumour development. Created with BioRender.com. ALD, alcohol-associated liver disease; ALDH2, aldehyde dehydrogenase 2; cGAS, cyclic GMP-AMP synthase; DRP1, dynamin-related protein 1; IFN, interferon; IRF, interferon regulatory factor; LD, lipid droplet; MFN, mitofusin; NAD+, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide-hydrogen; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1.

Credit

By Mengwei Niu, Xiaoli Wei, Xiaowen Ma, Wen-Xing Ding.

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License

CC BY-NC

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