Telomere length in offspring is determined by mitochondrial-nuclear communication at fertilization
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% O<sub>2</sub> 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.
Authors
- Darryl L. Russell (ORCID: https://orcid.org/0000-0002-4930-7658)
- Ryan Rose (ORCID: https://orcid.org/0000-0001-9732-1713)
- Alexander P. Sobinoff (ORCID: https://orcid.org/0000-0001-6679-5211)
- Mark A. Febbraio (ORCID: https://orcid.org/0000-0002-9296-4418)
- John Carroll (ORCID: https://orcid.org/0000-0001-9644-5861)
- Lee H. Wong (ORCID: https://orcid.org/0000-0002-4005-7330)
- Jadon Wells (ORCID: https://orcid.org/0009-0007-4809-827X)
- Sandra Piltz (ORCID: https://orcid.org/0000-0003-3386-8140)
- Rebecca L. Robker (ORCID: https://orcid.org/0000-0002-1538-4604)
- Yasmyn E. Winstanley (ORCID: https://orcid.org/0000-0002-0196-0965)
- Hilda A. Pickett (ORCID: https://orcid.org/0000-0002-9840-4841)
- Linda Wu (ORCID: https://orcid.org/0000-0002-8699-6341)
- Deepak Adhikari (ORCID: https://orcid.org/0000-0002-3404-8753)
- Hazel H. Szeto (ORCID: https://orcid.org/0000-0003-4021-5076)
- Qing-Hua Zhang (ORCID: https://orcid.org/0000-0001-7144-2330)
- Paul Q. Thomas (ORCID: https://orcid.org/0000-0002-5002-5770)
Institutions
- South Australia Pathology (AU)
- The University of Sydney (AU)
- Children's Medical Research Institute (AU)
- Discovery Institute (US)
- Australian Regenerative Medicine Institute (AU)
- Menlo School (US)
- Meta (United States) (US)
- St Andrew’s Hospital (AU)
- South Australian Health and Medical Research Institute (AU)
- Monash University (AU)
- The University of Adelaide (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-14
- DOI
- https://doi.org/10.1038/s41467-025-57794-7
- Citations
- 6
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 6.99
Funders
- Channel 7 Children's Research Foundation
- National Health and Medical Research Council