Loss of hepatic DRP1 exacerbates alcoholic hepatitis by inducing megamitochondria and mitochondrial maladaptation

Background and Aims: Increased megamitochondria formation and impaired mitophagy in hepatocytes have been linked to the pathogenesis of alcohol-associated liver disease (ALD). This study aims to determine the mechanisms by which alcohol consumption increases megamitochondria formation in the pathoge...

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Published inHepatology (Baltimore, Md.) Vol. 77; no. 1; pp. 159 - 175
Main Authors Ma, Xiaowen, Chen, Allen, Melo, Luma, Clemente-Sanchez, Ana, Chao, Xiaojuan, Ahmadi, Ali Reza, Peiffer, Brandon, Sun, Zhaoli, Sesaki, Hiromi, Li, Tiangang, Wang, Xiaokun, Liu, Wanqing, Bataller, Ramon, Ni, Hong-Min, Ding, Wen-Xing
Format Journal Article
LanguageEnglish
Published Hagerstown, MD Lippincott Williams & Wilkins 01.01.2023
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Summary:Background and Aims: Increased megamitochondria formation and impaired mitophagy in hepatocytes have been linked to the pathogenesis of alcohol-associated liver disease (ALD). This study aims to determine the mechanisms by which alcohol consumption increases megamitochondria formation in the pathogenesis of ALD. Approach and Results: Human alcoholic hepatitis (AH) liver samples were used for electron microscopy, histology, and biochemical analysis. Liver-specific dynamin-related protein 1 (DRP1; gene name DNM1L, an essential gene regulating mitochondria fission) knockout (L-DRP1 KO) mice and wild-type mice were subjected to chronic plus binge alcohol feeding. Both human AH and alcohol-fed mice had decreased hepatic DRP1 with increased accumulation of hepatic megamitochondria. Mechanistic studies revealed that alcohol feeding decreased DRP1 by impairing transcription factor EB-mediated induction of DNM1L. L-DRP1 KO mice had increased megamitochondria and decreased mitophagy with increased liver injury and inflammation, which were further exacerbated by alcohol feeding. Seahorse flux and unbiased metabolomics analysis showed alcohol intake increased mitochondria oxygen consumption and hepatic nicotinamide adenine dinucleotide (NAD+), acylcarnitine, and ketone levels, which were attenuated in L-DRP1 KO mice, suggesting that loss of hepatic DRP1 leads to maladaptation to alcohol-induced metabolic stress. RNA-sequencing and real-time quantitative PCR analysis revealed increased gene expression of the cGAS-stimulator of interferon genes (STING)-interferon pathway in L-DRP1 KO mice regardless of alcohol feeding. Alcohol-fed L-DRP1 KO mice had increased cytosolic mtDNA and mitochondrial dysfunction leading to increased activation of cGAS-STING-interferon signaling pathways and liver injury. Conclusion: Alcohol consumption decreases hepatic DRP1 resulting in increased megamitochondria and mitochondrial maladaptation that promotes AH by mitochondria-mediated inflammation and cell injury.
Bibliography:Abbreviations: AH, alcoholic hepatitis; ALD, alcohol-associated liver disease; ALT, alanine aminotransferase; C, complex; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; DRP1, dynamin-related protein 1; EM, electron microscopy; GSH, glutathione; IFN, interferon; IRF, interferon regulatory factor; KO, knockout; L-DRP1, liver-specific DRP1; MFN, mitofusin; mtDNA, mitochondrial DNA; NAD+, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide hydrogen; NPC, nonparenchyma cell; OPA1, optic atrophy 1; RNA-seq, RNA-sequencing; STING, stimulator of interferon genes; TFEB, transcription factor EB; WT, wild-type. Correspondence Wen-Xing Ding, Department of Pharmacology, Toxicology and Therapeutics The University of Kansas Medical Center, MS 1018, 3901 Rainbow Blvd., Kansas City, KS 66160, USA. Email: wxding@kumc.edu Funding informationNational Institute of Diabetes and Digestive and Kidney Diseases, Grant/ Award Number: R01 DK102142, R01 DK124612 and R01DK106540; National Institute of General Medical Sciences, Grant/Award Number: R35GM144103; National Institute on Aging, Grant/Award Number: R01 AG072895; National Institute on Alcohol Abuse and Alcoholism, Grant/Award Number: R21 AA026904, R37 AA020518, U01 AA024733, U01AA020821 and U01AA021908 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.hepjournal.com.
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AUTHOR CONTRIBUTIONS
Wen-Xing Ding conceived and supervised the project. Xiaowen Ma, Allen Chen, Xiaojuan Chao, Tiangang Li, and Hong-Min Ni performed experiments and analyzed the data. Xiaowen Ma, Hong-Min Ni, and Wen-Xing Ding conceived and designed the experiments. Ali Reza Ahmadi, Zhaoli Sun, and Hiromi Sesaki provided key reagents and discussed the manuscript. Wanqing Liu, Xiaokun Wang, Luma Melo, Ana Clemente-Sanchez, and Ramon Bataller analyzed the RNA-seq data. Xiaowen Ma and Wen-Xing Ding analyzed data and wrote the manuscript.
ISSN:0270-9139
1527-3350
1527-3350
DOI:10.1002/hep.32604