Carnitine acetyltransferase deficiency mediates mitochondrial dysfunction‐induced cellular senescence in dermal fibroblasts

Aging is accompanied by impaired mitochondrial function and accumulation of senescent cells. Mitochondrial dysfunction(definition) contributes to senescence(definition) by increasing the levels of reactive oxygen species and compromising energy metabolism. Senescent cells secrete a senescence-associated secretory phenotype (SASP) and stimulate chronic low-grade inflammation, ultimately inducing inflammaging(definition). Mitochondrial dysfunction and cellular senescence are two closely related telomere(definition) attrition, cellular senescence)." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">hallmarks of aging(definition); however, the key driver genes that link mitochondrial dysfunction and cellular senescence remain unclear. Here, we aimed to elucidate a novel role of carnitine acetyltransferase (CRAT) in the development of mitochondrial dysfunction and cellular senescence in dermal fibroblasts. Transcriptomic analysis of skin tissues from young and aged participants showed significantly decreased CRAT expression in intrinsically aged skin. CRAT downregulation in human dermal fibroblasts recapitulated mitochondrial changes in senescent cells and induced SASP secretion. Specifically, CRAT knockdown caused mitochondrial dysfunction, as indicated by increased oxidative stress, disruption of mitochondrial morphology, and a metabolic shift from oxidative phosphorylation to glycolysis. Mitochondrial damage induced the release of mitochondrial DNA into the cytosol, which activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NF-ĸB pathways to induce SASPs. Consistently, fibroblast-specific CRAT-knockout mice showed increased skin aging phenotypes in vivo, including decreased cell proliferation, increased SASP expression, increased inflammation, and decreased collagen density. Our results suggest that CRAT deficiency contributes to aging by mediating mitochondrial dysfunction-induced senescence.