Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease

Jun Dong, Li Chen, Fei Ye, Junhui Tang, Bing Liu, Jiacheng Lin, Pang-Hu Zhou, Bin Lu, Min Wu, Jia-Hong Lu, Jing-Jing He, Simone Engelender, Qingtao Meng, Zhiyin Song () and He He ()
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Jun Dong: Renmin Hospital of Wuhan University, Wuhan University
Li Chen: Renmin Hospital of Wuhan University, Wuhan University
Fei Ye: Renmin Hospital of Wuhan University, Wuhan University
Junhui Tang: Renmin Hospital of Wuhan University, Wuhan University
Bing Liu: Renmin Hospital of Wuhan University, Wuhan University
Jiacheng Lin: Renmin Hospital of Wuhan University, Wuhan University
Pang-Hu Zhou: Renmin Hospital of Wuhan University, Wuhan University
Bin Lu: University of South China
Min Wu: Renmin Hospital of Wuhan University, Wuhan University
Jia-Hong Lu: University of Macau
Jing-Jing He: Anhui Provincial Children’s Hospital
Simone Engelender: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology
Qingtao Meng: Renmin Hospital of Wuhan University, Wuhan University
Zhiyin Song: Renmin Hospital of Wuhan University, Wuhan University
He He: Renmin Hospital of Wuhan University, Wuhan University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.

Date: 2024
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DOI: 10.1038/s41467-023-44057-6

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