Telomere length in offspring is determined by mitochondrial-nuclear communication at fertilization

Yasmyn E. Winstanley, Ryan D. Rose, Alexander P. Sobinoff, Linda L. Wu, Deepak Adhikari, Qing-Hua Zhang, Jadon K. Wells, Lee H. Wong, Hazel H. Szeto, Sandra G. Piltz, Paul Q. Thomas, Mark A. Febbraio, John Carroll, Hilda A. Pickett, Darryl L. Russell and Rebecca L. Robker ()
Additional contact information
Yasmyn E. Winstanley: The University of Adelaide
Ryan D. Rose: The University of Adelaide
Alexander P. Sobinoff: University of Sydney
Linda L. Wu: The University of Adelaide
Deepak Adhikari: Monash University
Qing-Hua Zhang: Monash University
Jadon K. Wells: University of Sydney
Lee H. Wong: Monash University
Hazel H. Szeto: Social Profit Network
Sandra G. Piltz: The University of Adelaide
Paul Q. Thomas: The University of Adelaide
Mark A. Febbraio: Monash University
John Carroll: Monash University
Hilda A. Pickett: University of Sydney
Darryl L. Russell: The University of Adelaide
Rebecca L. Robker: The University of Adelaide

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract The initial setting of telomere length during early life in each individual has a major influence on lifetime risk of aging-associated diseases; however there is limited knowledge of biological signals that regulate inheritance of telomere length, and whether it is modifiable is not known. We now show that when mitochondrial activity is disrupted in mouse zygotes, via exposure to 20% O2 or rotenone, telomere elongation between the 8-cell and blastocyst stage is impaired, with shorter telomeres apparent in the pluripotent Inner Cell Mass (ICM) and persisting after organogenesis. Identical defects of elevated mtROS in zygotes followed by impaired telomere elongation, occurred with maternal obesity or advanced age. We further demonstrate that telomere elongation during ICM formation is controlled by mitochondrial-nuclear communication at fertilization. Using mitochondrially-targeted therapeutics (BGP-15, MitoQ, SS-31, metformin) we demonstrate that it is possible to modulate the preimplantation telomere resetting process and restore deficiencies in neonatal telomere length.

Date: 2025
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DOI: 10.1038/s41467-025-57794-7

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