Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age

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.

Deconvolution of HIV-1 Mutational Signatures Reveals Dominant and Donor-Specific APOBEC3-Associated Mutagenesis Across Anatomical Compartments
M. Soleimanpour, N. Haghjoo, J. lehle +5
bioRxiv23 Sep 2026PreprintCC BY-NDFull textGenetics & genomicsbioRxiv
Scalable saturation mutagenesis reveals gene regulatory architecture and rare variant effects
H. Yuan, X. Huang, B. Auerbach +3
bioRxiv30 Sep 2026PreprintCC BY-NC-NDFull textGenetics & genomicsbioRxiv
Modified crRNA variants for precise targeting of point mutations in human mitochondrial DNA by CRISPR-Cas12a
Nikita Shebanov, Anne-Marie Heckel, Natalia Nikitchina +5
HAL9 Sep 2026PreprintCC BYFull textMolecular biology & gene regulation General biologyHALbioRxiv
Single Cell Proteomics reveals partial uncoupling of the Glycerol-3-Phosphate shuttle to compensate for Electron Transport Chain dysfunction in Alexander Disease GFAP mutations
C. A. van Gelder, E. Daoutsali, Y. Attour +8
bioRxiv5 Oct 2026PreprintAll rights reservedFull textNeurosciencebioRxiv
Modeling ATN1 mutations in human iPSCs reveals early developmental roles of atrophin-1
E. Kozlowska, N. Ziojla, B. Nowak +6
bioRxiv30 Oct 2026PreprintCC BYFull textCell biologybioRxiv

Cite

BibTeX RIS

BibTeX

@misc{shemtov2026temporal,
  title = {{Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age}},
  author = {S. J. Shemtov and E. Hwang and C. S. Chung and H. Anson and L. Carrillo and S. Lee and I. Vorobyova and J. Wan and S. R. Kennedy and A. R. Vandiver and B. M. Verheijen and W. Cohn and B. A. Benayoun and M. A. Thorwald and P. Cohen and J. Wanagat and J.-F. Gout and M. Vermulst},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.24.754271},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754271v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age
AU  - S. J. Shemtov
AU  - E. Hwang
AU  - C. S. Chung
AU  - H. Anson
AU  - L. Carrillo
AU  - S. Lee
AU  - I. Vorobyova
AU  - J. Wan
AU  - S. R. Kennedy
AU  - A. R. Vandiver
AU  - B. M. Verheijen
AU  - W. Cohn
AU  - B. A. Benayoun
AU  - M. A. Thorwald
AU  - P. Cohen
AU  - J. Wanagat
AU  - J.-F. Gout
AU  - M. Vermulst
PY  - 2026
DA  - 2026/09/24
PB  - bioRxiv
DO  - 10.64898/2026.09.24.754271
UR  - https://www.biorxiv.org/content/10.64898/2026.09.24.754271v1
AB  - 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.
ER  -

Abstract

Related

Cite