Mitochondrial subpopulations in oocytes and cumulus cells exhibit distinct age-associated changes and selective plasticity in response to NMN supplementation
- 1Department of Biology, Northeastern University, Boston, MA USA
- 2SauveBio Inc, Worcester, MA USA
- 3University of Miami Miller School of Medicine, Miami, FL USA
Abstract
Background: Mitochondrial dysfunction is a leading contributor to the decline in oocyte quality associated with maternal aging. Prior investigations of mitochondrial function in the ovarian follicle have largely treated the mitochondrial pool as a homogeneous population, reporting aggregate values that may obscure biologically meaningful differences between distinct mitochondrial subpopulations. The present study addresses this limitation by characterizing mitochondrial subpopulation dynamics in oocytes and cumulus granulosa cells at single-organelle resolution using fluorescence-activated mitochondria sorting (FAMS).
Results: Analysis of the aggregate mitochondrial population in mouse oocytes revealed no significant age-associated differences in mitochondrial DNA copy number or membrane potential, a result that would previously have been interpreted as evidence of minimal age-related mitochondrial change. Subpopulation analysis revealed this conclusion to be incomplete: aged oocytes showed significantly elevated mitochondrial DNA copy number specifically within the high membrane potential and small mitochondrial subpopulations, with no significant differences in the low membrane potential or large subpopulations. NMN supplementation normalized mitochondrial DNA copy number in the high membrane potential and small subpopulations toward young levels while producing an opposing effect in large mitochondria, demonstrating subpopulation-specific rather than uniform rejuvenation. In cumulus cells, significant age-associated changes were detectable at the aggregate level, including a reduction in mitochondrial DNA copy number and an elevation in membrane potential, and subpopulation analysis further resolved these findings. The age-associated reduction in cumulus cell mitochondrial DNA copy number was driven predominantly by the high membrane potential subpopulation. NMN supplementation exerted opposing effects on small and large cumulus cell mitochondrial subpopulations, increasing mitochondrial DNA copy number above both young and aged levels in small mitochondria while further reducing it below aged levels in large mitochondria.
Conclusions: Viewing the mitochondrial pool as a heterogeneous mixture of functionally distinct subpopulations rather than a uniform population reveals age-associated alterations in oocytes and cumulus cells that are undetectable by aggregate analysis. NMN supplementation exerts subpopulation-specific effects in both cell types, identifying specific mitochondrial subtypes as more precise targets for future mechanistic investigation of age-associated infertility than the mitochondrial pool considered in aggregate.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13048-026-02223-6.
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BibTeX
@article{piasecki2026mitochondrial,
title = {{Mitochondrial subpopulations in oocytes and cumulus cells exhibit distinct age-associated changes and selective plasticity in response to NMN supplementation}},
author = {Andrew J. Piasecki and Hannah Sheehan and Paula Ledo Hopgood and Jonathan L. Tilly and Dori C. Woods},
journal = {Journal of Ovarian Research},
year = {2026},
month = aug,
doi = {10.1186/s13048-026-02223-6},
url = {https://doi.org/10.1186/s13048-026-02223-6},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mitochondrial subpopulations in oocytes and cumulus cells exhibit distinct age-associated changes and selective plasticity in response to NMN supplementation
AU - Andrew J. Piasecki
AU - Hannah Sheehan
AU - Paula Ledo Hopgood
AU - Jonathan L. Tilly
AU - Dori C. Woods
PY - 2026
DA - 2026/08/07
JO - Journal of Ovarian Research
DO - 10.1186/s13048-026-02223-6
UR - https://doi.org/10.1186/s13048-026-02223-6
AB - Background: Mitochondrial dysfunction is a leading contributor to the decline in oocyte quality associated with maternal aging. Prior investigations of mitochondrial function in the ovarian follicle have largely treated the mitochondrial pool as a homogeneous population, reporting aggregate values that may obscure biologically meaningful differences between distinct mitochondrial subpopulations. The present study addresses this limitation by characterizing mitochondrial subpopulation dynamics in oocytes and cumulus granulosa cells at single-organelle resolution using fluorescence-activated mitochondria sorting (FAMS). Results: Analysis of the aggregate mitochondrial population in mouse oocytes revealed no significant age-associated differences in mitochondrial DNA copy number or membrane potential, a result that would previously have been interpreted as evidence of minimal age-related mitochondrial change. Subpopulation analysis revealed this conclusion to be incomplete: aged oocytes showed significantly elevated mitochondrial DNA copy number specifically within the high membrane potential and small mitochondrial subpopulations, with no significant differences in the low membrane potential or large subpopulations. NMN supplementation normalized mitochondrial DNA copy number in the high membrane potential and small subpopulations toward young levels while producing an opposing effect in large mitochondria, demonstrating subpopulation-specific rather than uniform rejuvenation. In cumulus cells, significant age-associated changes were detectable at the aggregate level, including a reduction in mitochondrial DNA copy number and an elevation in membrane potential, and subpopulation analysis further resolved these findings. The age-associated reduction in cumulus cell mitochondrial DNA copy number was driven predominantly by the high membrane potential subpopulation. NMN supplementation exerted opposing effects on small and large cumulus cell mitochondrial subpopulations, increasing mitochondrial DNA copy number above both young and aged levels in small mitochondria while further reducing it below aged levels in large mitochondria. Conclusions: Viewing the mitochondrial pool as a heterogeneous mixture of functionally distinct subpopulations rather than a uniform population reveals age-associated alterations in oocytes and cumulus cells that are undetectable by aggregate analysis. NMN supplementation exerts subpopulation-specific effects in both cell types, identifying specific mitochondrial subtypes as more precise targets for future mechanistic investigation of age-associated infertility than the mitochondrial pool considered in aggregate. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13048-026-02223-6.
SN - 1757-2215
ER -