Theranostics 2022; 12(7):3237-3250. doi:10.7150/thno.69826 This issue Cite

Research Paper

AGK regulates the progression to NASH by affecting mitochondria complex I function

Nan Ding1*, Kang Wang3*, Haojie Jiang1, Mina Yang1, Lin Zhang1, Xuemei Fan1, Qiang Zou2, Jianxiu Yu1, Hui Dong3, Shuqun Cheng3✉, Yanyan Xu1✉, Junling Liu1✉

1. Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3. Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
*These authors contributed equally to this work.

Citation:
Ding N, Wang K, Jiang H, Yang M, Zhang L, Fan X, Zou Q, Yu J, Dong H, Cheng S, Xu Y, Liu J. AGK regulates the progression to NASH by affecting mitochondria complex I function. Theranostics 2022; 12(7):3237-3250. doi:10.7150/thno.69826. https://www.thno.org/v12p3237.htm
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Abstract

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Background: Impaired mitochondrial function contributes to non-alcoholic steatohepatitis (NASH). Acylglycerol kinase (AGK) is a subunit of the translocase of the mitochondrial inner membrane 22 (TIM22) protein import complex. AGK mutation is the leading cause of Sengers syndrome, characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, lactic acidosis, and liver dysfunction. The potential roles and mechanisms of AGK in NASH are not yet elucidated.

Methods: Hepatic-specific AGK-deficient mice and AGK G126E mutation (AGK kinase activity arrest) mice were on a choline-deficient and high-fat diet (CDAHFD) and a methionine choline-deficient diet (MCD). The mitochondrial function and the molecular mechanisms underlying AGK were investigated in the pathogenesis of NASH.

Results: The levels of AGK were significantly downregulated in human NASH liver samples. AGK deficiency led to severe liver damage and lipid accumulation in mice. Aged mice lacking hepatocyte AGK spontaneously developed NASH. AGK G126E mutation did not affect the structure and function of hepatocytes. AGK deficiency, but not AGK G126E mice, aggravated CDAHFD- and MCD-induced NASH symptoms. AGK deficiency-induced liver damage could be attributed to hepatic mitochondrial dysfunction. The mechanism revealed that AGK interacts with mitochondrial respiratory chain complex I subunits, NDUFS2 and NDUFA10, and regulates mitochondrial fatty acid metabolism. Moreover, the AGK DGK domain might directly interact with NDUFS2 and NDUFA10 to maintain the hepatic mitochondrial respiratory chain complex I function.

Conclusions: The current study revealed the critical roles of AGK in NASH. AGK interacts with mitochondrial respiratory chain complex I to maintain mitochondrial integrity via the kinase-independent pathway.

Keywords: mitochondrial respiratory chain, NDUFS2, fatty acid metabolism, mitochondrial ROS


Citation styles

APA
Ding, N., Wang, K., Jiang, H., Yang, M., Zhang, L., Fan, X., Zou, Q., Yu, J., Dong, H., Cheng, S., Xu, Y., Liu, J. (2022). AGK regulates the progression to NASH by affecting mitochondria complex I function. Theranostics, 12(7), 3237-3250. https://doi.org/10.7150/thno.69826.

ACS
Ding, N.; Wang, K.; Jiang, H.; Yang, M.; Zhang, L.; Fan, X.; Zou, Q.; Yu, J.; Dong, H.; Cheng, S.; Xu, Y.; Liu, J. AGK regulates the progression to NASH by affecting mitochondria complex I function. Theranostics 2022, 12 (7), 3237-3250. DOI: 10.7150/thno.69826.

NLM
Ding N, Wang K, Jiang H, Yang M, Zhang L, Fan X, Zou Q, Yu J, Dong H, Cheng S, Xu Y, Liu J. AGK regulates the progression to NASH by affecting mitochondria complex I function. Theranostics 2022; 12(7):3237-3250. doi:10.7150/thno.69826. https://www.thno.org/v12p3237.htm

CSE
Ding N, Wang K, Jiang H, Yang M, Zhang L, Fan X, Zou Q, Yu J, Dong H, Cheng S, Xu Y, Liu J. 2022. AGK regulates the progression to NASH by affecting mitochondria complex I function. Theranostics. 12(7):3237-3250.

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