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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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Project description:The goal of this analysis was to utilize microarray profiling to identify basal alterations in gene expression in response to TFAM depletion and mtDNA stress. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein, TFAM (transcription factor A,mitochondrial), regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signaling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity. Murine embryonic fibroblasts were isolated from wild-type or Tfam+/- E13.5 littermate embryos. RNA from passage-matched wild-type and Tfam+/- MEF lines was extracted in duplicate and hybridized onto Affymetrix microarrays. Four arrays were performed in total with two technical replicates per genotype.

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

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