The mitochondrial-derived peptide MOTS-c improves bioenergetics in aging-associated granulosa cells and oocytes
8 affiliations
- 1Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- 2Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
- 3Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan
- 4National Museum of Marine Biology & Aquarium, Pingtung, Taiwan
- 5School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
- 6Center of General Education, Cheng Shiu University, Kaohsiung, Taiwan
- 7Sundial Initiative, Palo Alto, California, USA
- 8Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
Abstract
Ovarian aging compromises granulosa cell function, mitochondrial homeostasis, metabolism, and oocyte quality. We investigated whether the mitochondrial-derived peptide MOTS-c mitigates these defects using an aging-associated HGL5 granulosa cell model, ex vivo oocytes from young and aged mice, and public granulosa cell transcriptomic datasets. In HGL5 cells, MOTS-c increased mitochondrial mass and ATP-associated fluorescence without increasing cellular or mitochondrial reactive oxygen species, while mass-normalized membrane potential remained unchanged. Seahorse analysis showed increased ATP-linked and maximal respiration and spare respiratory capacity, reduced proton leak, and unchanged basal respiration. MOTS-c also remodeled the expression of enzymes involved in glycolysis, lactate–pyruvate handling, and pyruvate–TCA metabolism. Although fission markers were largely unchanged, MOTS-c increased the levels of proteins associated with antioxidant defense, mitochondrial transport, cell junctions, adhesion signaling, and granulosa cell function, including NRF2, phosphorylated AIFM1, RHOT1, KIF5B, ZO-1, E-cadherin, phosphorylated FAK, and AMH. Aged oocytes exhibited reduced polar body extrusion, increased DCFDA fluorescence, and decreased CMXRos intensity. Ex vivo MOTS-c treatment increased post-culture first polar body positivity and mitochondria-associated fluorescence while reducing oxidative stress-associated fluorescence, although outcomes remained below young-reference levels. Reanalysis of human folliculogenesis and nonhuman primate ovarian aging datasets further revealed a young-enriched trend in the MOTS-c-associated metabolic program. These findings suggest that MOTS-c improves metabolic, mitochondrial, and structural features of aging-associated granulosa cells and enhances maturation-associated outcomes in aged oocytes, supporting further investigation of MOTS-c-based strategies for reproductive aging.
Lay summary: As women age, the quality of their eggs declines, which is a major contributor to age-related infertility. Eggs are supported by neighboring ‘helper’ cells called granulosa cells, which act like a support crew that supplies the egg with the energy it needs to mature. These helper cells contain mitochondria, tiny energy-generating structures often called the cell’s ‘powerhouses’, and with age these powerhouses become less efficient, leaving eggs with less support than they need. This study tested whether MOTS-c, a small molecule naturally produced by mitochondria, could restore the function of these aging helper cells. In laboratory experiments using aged human granulosa cells and eggs from aged mice, MOTS-c boosted energy production and helped maintain cell structure. It was also associated with improved egg maturation compared with that in untreated aged eggs, although treated eggs did not fully reach the maturation levels seen in young mice. These findings are from laboratory and animal experiments, not from women, and this study did not test whether MOTS-c affects fertilization, embryo development, or live birth. Further research is needed before any conclusions can be drawn about its relevance to human fertility.
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BibTeX
@article{tsui2026mitochondrialderived,
title = {{The mitochondrial-derived peptide MOTS-c improves bioenergetics in aging-associated granulosa cells and oocytes}},
author = {Kuan-Hao Tsui and Shih-Hsuan Cheng and Li-Te Lin and Pei-Hsuan Lin and Boyang Wang and Zhi-Hong Wen and Chia-Jung Li},
journal = {Reproduction \& Fertility},
year = {2026},
month = oct,
doi = {10.1530/raf-26-0161},
url = {https://doi.org/10.1530/raf-26-0161},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The mitochondrial-derived peptide MOTS-c improves bioenergetics in aging-associated granulosa cells and oocytes
AU - Kuan-Hao Tsui
AU - Shih-Hsuan Cheng
AU - Li-Te Lin
AU - Pei-Hsuan Lin
AU - Boyang Wang
AU - Zhi-Hong Wen
AU - Chia-Jung Li
PY - 2026
DA - 2026/10/27
JO - Reproduction & Fertility
DO - 10.1530/raf-26-0161
UR - https://doi.org/10.1530/raf-26-0161
AB - Ovarian aging compromises granulosa cell function, mitochondrial homeostasis, metabolism, and oocyte quality. We investigated whether the mitochondrial-derived peptide MOTS-c mitigates these defects using an aging-associated HGL5 granulosa cell model, ex vivo oocytes from young and aged mice, and public granulosa cell transcriptomic datasets. In HGL5 cells, MOTS-c increased mitochondrial mass and ATP-associated fluorescence without increasing cellular or mitochondrial reactive oxygen species, while mass-normalized membrane potential remained unchanged. Seahorse analysis showed increased ATP-linked and maximal respiration and spare respiratory capacity, reduced proton leak, and unchanged basal respiration. MOTS-c also remodeled the expression of enzymes involved in glycolysis, lactate–pyruvate handling, and pyruvate–TCA metabolism. Although fission markers were largely unchanged, MOTS-c increased the levels of proteins associated with antioxidant defense, mitochondrial transport, cell junctions, adhesion signaling, and granulosa cell function, including NRF2, phosphorylated AIFM1, RHOT1, KIF5B, ZO-1, E-cadherin, phosphorylated FAK, and AMH. Aged oocytes exhibited reduced polar body extrusion, increased DCFDA fluorescence, and decreased CMXRos intensity. Ex vivo MOTS-c treatment increased post-culture first polar body positivity and mitochondria-associated fluorescence while reducing oxidative stress-associated fluorescence, although outcomes remained below young-reference levels. Reanalysis of human folliculogenesis and nonhuman primate ovarian aging datasets further revealed a young-enriched trend in the MOTS-c-associated metabolic program. These findings suggest that MOTS-c improves metabolic, mitochondrial, and structural features of aging-associated granulosa cells and enhances maturation-associated outcomes in aged oocytes, supporting further investigation of MOTS-c-based strategies for reproductive aging. Lay summary: As women age, the quality of their eggs declines, which is a major contributor to age-related infertility. Eggs are supported by neighboring ‘helper’ cells called granulosa cells, which act like a support crew that supplies the egg with the energy it needs to mature. These helper cells contain mitochondria, tiny energy-generating structures often called the cell’s ‘powerhouses’, and with age these powerhouses become less efficient, leaving eggs with less support than they need. This study tested whether MOTS-c, a small molecule naturally produced by mitochondria, could restore the function of these aging helper cells. In laboratory experiments using aged human granulosa cells and eggs from aged mice, MOTS-c boosted energy production and helped maintain cell structure. It was also associated with improved egg maturation compared with that in untreated aged eggs, although treated eggs did not fully reach the maturation levels seen in young mice. These findings are from laboratory and animal experiments, not from women, and this study did not test whether MOTS-c affects fertilization, embryo development, or live birth. Further research is needed before any conclusions can be drawn about its relevance to human fertility.
SN - 2633-8386
ER -