Year: 2026
Type: preprint
Abstract: ABSTRACT Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo . These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.
Authors: Sarah J. Shemtov, Eric Hwang, Claire S. Chung, Herbert Anson, Lucy Carrillo, Sangmin Lee, Ivetta Vorobyova, Junxiang Wan, Scott R. Kennedy, Amy R. Vandiver, Bert M. Verheijen, Whitaker Cohn, Bérénice A. Benayoun, Max A. Thorwald, Pinchas Cohen, Jonathan Wanagat, Jean-François Gout, Marc Vermulst
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Triggering the Selective Removal of Deleterious mtDNA Mutations from Mammalian Cells, Targeting the IGF-1/insulin signaling pathway to treat mtDNA disease, Investigating the landscape and genetic architecture of germline mutagenesis, DNA-damage-induced transcription errors provide a constant stream of amyloid and prion-like proteins in human cells, Temporal control of mitochondrial mutagenesis
OpenAlex ID: W7214526774