Letter to the Editor: Loss of hepatic DRP1 exacerbates alcoholic hepatitis by inducing megamitochondria and mitochondrial maladaptation

To the editor, We followed with interest the article by Ma et al1 reporting that DRP1 deficiency led to mitochondrial dysfunction and increased mitochondrial DNA (mtDNA) release, resulting in activation of the cGAS-STING signaling pathway and exacerbation of alcohol-induced liver inflammatory injury. However, we believe there are some crucial aspects concerning the pathological mechanism of cGAS-STING signaling–mediated immune response that require further clarification and discussion. First, the study reported that cGAS-STING signaling is activated, and the expression levels of STING, p-TBK1, and p-IRF3 involved in this pathway were increased in patients with alcoholic hepatitis. Nevertheless, alcohol feeding did not activate the cGAS-STING pathway in mice regardless of DRP1 deficiency. In addition, their downstream gene and serum mtDNA levels were also not affected, and loss of DRP1 even caused some genes' expression levels to be markedly reduced by alcohol intake. However, there is no clear explanation regarding these contradictory results between patient and mice. Therefore, it is necessary to reinspect the reliability of the present experimental model. Second, the current study only detected mtDNA accumulation in mice serum and hepatocyte cytoplasm, while the level of mtDNA released by hepatocytes into the extracellular space was not determined. Of note, previous studies have demonstrated that stress-induced cytosolic leakage of mtDNA plays a crucial role in both intracellular and intercellular activation of cGAS-STING signaling.2 Thus, apart from confirming cytoplasmic mtDNA accumulation, it is also important to investigate the extracellular release level of alcohol-induced hepatocellular mtDNA to further add credibility to the results of intercellular cGAS-STING activation. Third, in this research, there is no clear conclusion whether cGAS-STING is activated in hepatocyte or macrophage/KCs. The investigators only confirmed that cGAS was mainly expressed in the nucleus of these cells. In Supplemental Figure S11B of Ma et al,1 it seems that nonparenchymal cell and KCs are the major cell types in cGAS-STING signaling activation, since this pathway-related protein can be hardly detected in hepatocytes. However, a previous study showed that hepatocyte was the primary cell type responsible for the alcohol-induced cGAS-STING activation.3 Therefore, the degree of contribution of liver parenchymal cells, macrophages, and nonparenchymal cells to DRP1 deficiency or alcohol-induced cGAS-STING activation should be further clarified. In conclusion, this study provides a new insight into the understanding of mitochondrial dynamics in the innate immune response–associated pathogenesis of alcohol-associated liver disease. However, further studies are needed regarding the above issues to solidify the current conclusions.