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

Abstract

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.

Mitochondrial respiratory chain activity is associated with severity, corticosteroid response and prognosis of alcoholic hepatitis

“…It has been previously reported that mitochondrial morphology and function are affected in different ways in distinct chronic liver diseases, such as ALD 8,[26][27][28] and non-alcoholic fatty liver disease (NAFLD). 29,30 Regarding ALD, only a few studies have directly measured the activity of the MRC enzymatic complexes in the liver tissue of ALD animal models [31][32][33] and indirectly in humans by measuring the decarboxylation of ketoisocaproate by a breath test.…”

Giant mitochondria in human liver disease

“…In brief, the altered function of ‘mitochondrial contact sites and cristae organising system (MICOS)’ at the cristae junctions seem to be pivotal in this dynamic process of reshaping the mitochondrial inner membrane. Recently, Ma et al 49 demonstrated lower levels of liver‐specific dynamin‐related protein (DRP1) in human alcoholic hepatitis, including in alcohol‐fed mice. In this study, TEM investigation showed the presence of unusually enlarged mitochondria described as megamitochondria, but clear inclusions were absent.…”

Insights of mitochondrial involvement in alcoholic fatty liver disease

“…Such alteration is coupled with reduced hepatocyte injury as an adaptive mechanism preserving the mitochondria from fission and mitophagy (Palma et al, 2019). The Gao binge ethanol administered parkin‐KO and DRP1‐KO mice and human ASH subjects containing reduced hepatic DRP‐1 and mitofusin 1 & 2 displayed significantly reduced mitophagy, increased liver injury, and accumulation of damaged and swallow mitochondria, whereas the restoration of DRP1 via overexpression reduced the megamitochondria count with increased LC3‐II but not steatosis (Ma et al, 2023; Williams et al, 2015). This reduction in the expression of DRP1, MFN1&2 is due to the reduction in hepatic transcription factor EB (TFEB).…”