Carnitine acetyltransferase deficiency mediates mitochondrial dysfunction-induced cellular senescence in dermal fibroblasts.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro and animal knockout study with observational human tissue transcriptomics
PubMed 37828898 · doi:10.1111/acel.14000
What was done
Transcriptomic analysis was performed on skin tissues from young and aged human donors to evaluate carnitine acetyltransferase (CRAT) expression. Mechanistic experiments used human dermal fibroblasts with CRAT knockdown to assess mitochondrial morphology, oxidative stress, metabolic pathway shifts, cytosolic release of mitochondrial DNA (mtDNA), and activation of the cGAS-STING and NF-κB pathways. In vivo, fibroblast-specific CRAT-knockout mice were evaluated for skin aging phenotypes, including cell proliferation, SASP expression, inflammation, and collagen density.
What was found
No quantitative figures, sample sizes, or p-values were reported in the abstract. Directional findings reported: - CRAT expression was significantly decreased in intrinsically aged human skin. - CRAT knockdown in human dermal fibroblasts increased oxidative stress, disrupted mitochondrial morphology, shifted metabolism from oxidative phosphorylation to glycolysis, caused cytosolic mtDNA release, and activated cGAS-STING and NF-κB pathways to stimulate SASP secretion. - Fibroblast-specific CRAT-knockout mice showed decreased cell proliferation, increased SASP expression, increased inflammation, and decreased collagen density in skin.
Why it matters
This study identifies CRAT downregulation as a mechanistic link between mitochondrial dysfunction, cGAS-STING innate immune signaling, and senescence in dermal fibroblasts, suggesting a possible pathway for skin aging research.
Limits
Sample sizes for human tissue donors, cell cultures, and animal cohorts are omitted in the abstract, as are quantitative effect sizes and statistical parameters. The evidence is derived predominantly from in vitro gene silencing and transgenic mouse models, which may not directly translate to human clinical interventions or skin aging therapeutics.
Cited by
- supports As ATP demand on a cell increases, aging and disease lead to an earlier shift from oxidative phosphorylation to glycolysis.