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Butyrate extends health and lifespan in mice with mitochondrial dysfunction

ABSTRACT: Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. To investigate novel strategies that alleviate mitochondrial dysfunction, we have generated a tamoxifen-inducible, knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance, under the control of the ubiquitin gene promoter — Tfamfl/flUbCre‑ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share deficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin (TB), a butyrate precursor, delay multiple signs of multimorbidity extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE304464 | GEO | 2026/02/19

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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Butyrate extends health and lifespan in mice with mitochondrial dysfunction

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