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The SIRT3-DsbA-L-TFAM Axis Suppresses Liver cGAS Signaling and MASH Progression in Male Mice

ABSTRACT: While mitochondrial dysfunction is implicated in metabolic dysfunction associated steatohepatitis (MASH), the precise underlying mechanisms remain obscure. Here, we identify the SIRT3-DsbA-L-TFAM axis as a crucial suppressor for mitochondrial stress-induced cGAS activation in the hepatocytes, thereby alleviating MASH in mice. SIRT3 facilitates the deacetylation of Disulfide-bond-A oxidoreductase-like protein (DsbA-L) at lysine residues (Lys165, Lys167, and Lys177), which promotes the interaction between DsbA-L and mitochondrial transcription factor A (TFAM), essential for the preservation of mitochondrial integrity and function. Hepatocyte-specific knockout of SIRT3 or DsbA-L in male mice promoted mitochondrial DNA release into the cytosol, resulting in activation of the cGAS-STING pathway and exacerbation of MASH characteristics. Conversely, hepatocyte-specific knockout of cGAS or overexpression of DsbA-L mitigated diet- and SIRT3 deficiency-induced MASH progression. Our study underscores the clinical significance of targeting SIRT3 and cGAS as pivotal therapeutic avenues to inhibit the progression of MASH.

ORGANISM(S): Mus musculus

PROVIDER: GSE281667 | GEO | 2024/11/30

REPOSITORIES: GEO

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The SIRT3-DsbA-L-TFAM Axis Suppresses Liver cGAS Signaling and MASH Progression in Male Mice

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