{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T21:31:42Z","timestamp":1768253502681,"version":"3.49.0"},"reference-count":47,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T00:00:00Z","timestamp":1708905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Merck SA, FERTIMPROVE PROJECT","award":["IT0230"],"award-info":[{"award-number":["IT0230"]}]},{"name":"Merck SA, FERTIMPROVE PROJECT","award":["SFRH\/BD\/144561\/2019"],"award-info":[{"award-number":["SFRH\/BD\/144561\/2019"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT)","award":["IT0230"],"award-info":[{"award-number":["IT0230"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT)","award":["SFRH\/BD\/144561\/2019"],"award-info":[{"award-number":["SFRH\/BD\/144561\/2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Age-related changes in the mitochondrial status of human cumulus cells (hCCs) impact oocyte quality; however, the relationship between hCC mitochondrial (dys)function and reproductive aging remains poorly understood. This study aimed to establish the interplay between hCC mitochondrial dysfunction and women\u2019s reproductive potential. In this investigation, 266 women were enrolled and categorized into two groups based on their age: a young group (&lt;35 years old) and an advanced maternal age (AMA) group (\u226535 years old). Comprehensive analysis of reproductive outcomes was conducted in our population. Various mitochondrial-related parameters were analyzed across distinct subsets. Specifically, mitochondrial membrane potential (\u2206\u03a8m) and mitochondrial mass were examined in 53 samples, mtDNA content in 25 samples, protein levels in 23 samples, bioenergetic profiles using an XF24 Extracellular Flux Analyzer in 6 samples, and levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP) in 39 and 43 samples, respectively. In our study, the reproductive potential of AMA women sharply decreased, as expected. Additionally, an impairment in the mitochondrial function of hCCs in older women was observed; however, no differences were found in terms of mitochondrial content. Regarding oxidative phosphorylation, metabolic profiling of hCCs from AMA women indicated a decrease in respiratory capacity, which was correlated with an age-dependent decrease in the ATP synthase (ATP5A1) protein level. However, intracellular ROS and ATP levels did not differ between groups. In conclusion, our study indicates that age-related dysfunction in hCCs is associated with impaired mitochondrial function, and, although further studies are required, ATP synthase could be relevant in this impairment.<\/jats:p>","DOI":"10.3390\/biom14030281","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T11:31:21Z","timestamp":1708947081000},"page":"281","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mitochondrial Dysfunction in Advanced Maternal Aged Cumulus Cells: A Possible Link to ATP Synthase Impairment?"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6669-4303","authenticated-orcid":false,"given":"Sandra","family":"Almeida-Reis","sequence":"first","affiliation":[{"name":"University of Coimbra, Institute for Interdisciplinary Research, PhD Programme in Experimental Biology and Biomedicine (PDBEB), 3030-789 Coimbra, Portugal"},{"name":"University of Coimbra, CNC-UC\u2014Centre for Neuroscience and Cell Biology, 3004-504 Coimbra, Portugal"},{"name":"University of Coimbra, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, 3004-504 Coimbra, Portugal"}]},{"given":"Alexandra","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Unit, Centro Hospitalar e Universit\u00e1rio de Coimbra, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal"},{"name":"CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-001 Covilh\u00e3, Portugal"}]},{"given":"Concei\u00e7\u00e3o","family":"Dias","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Unit, Centro Hospitalar e Universit\u00e1rio de Coimbra, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal"}]},{"given":"Raquel","family":"Brito","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Unit, Centro Hospitalar e Universit\u00e1rio de Coimbra, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal"}]},{"given":"Rita","family":"Silva","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Unit, Centro Hospitalar e Universit\u00e1rio de Coimbra, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal"}]},{"given":"Teresa","family":"Almeida-Santos","sequence":"additional","affiliation":[{"name":"University of Coimbra, CNC-UC\u2014Centre for Neuroscience and Cell Biology, 3004-504 Coimbra, Portugal"},{"name":"University of Coimbra, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, 3004-504 Coimbra, Portugal"},{"name":"Reproductive Medicine Unit, Centro Hospitalar e Universit\u00e1rio de Coimbra, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal"},{"name":"University of Coimbra, Faculty of Medicine, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal"},{"name":"Eugin Coimbra, Rua Filipe Hodart 12, 3000-185 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1172-4018","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Ramalho-Santos","sequence":"additional","affiliation":[{"name":"University of Coimbra, CNC-UC\u2014Centre for Neuroscience and Cell Biology, 3004-504 Coimbra, Portugal"},{"name":"University of Coimbra, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, 3004-504 Coimbra, Portugal"},{"name":"University of Coimbra, Department of Life Sciences, Cal\u00e7ada Martim de Freitas, 3000-456 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4190-6138","authenticated-orcid":false,"given":"Ana Paula","family":"Sousa","sequence":"additional","affiliation":[{"name":"University of Coimbra, CNC-UC\u2014Centre for Neuroscience and Cell Biology, 3004-504 Coimbra, Portugal"},{"name":"University of Coimbra, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, 3004-504 Coimbra, Portugal"},{"name":"Reproductive Medicine Unit, Centro Hospitalar e Universit\u00e1rio de Coimbra, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal"},{"name":"Eugin Coimbra, Rua Filipe Hodart 12, 3000-185 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, H., Fan, C., Mubarik, S., Nabi, G., and Ping, Y.X. (2022). The trend in delayed childbearing and its potential consequences on pregnancy outcomes: A single center 9-years retrospective cohort study in Hubei, China. BMC Pregnancy Childbirth, 22.","DOI":"10.1186\/s12884-022-04807-8"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1016\/j.fertnstert.2016.02.028","article-title":"Impact of female age and nulligravidity on fecundity in an older reproductive age cohort","volume":"105","author":"Steiner","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Esencan, E., Beroukhim, G., and Seifer, D.B. (2022). Age-related changes in Folliculogenesis and potential modifiers to improve fertility outcomes\u2014A narrative review. Reprod. Biol. Endocrinol., 20.","DOI":"10.1186\/s12958-022-01033-x"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101378","DOI":"10.1016\/j.arr.2021.101378","article-title":"Mitochondria: Their relevance during oocyte ageing","volume":"70","author":"Haigis","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1007\/s43032-022-01046-2","article-title":"Bioinformatic Analysis of Human Cumulus Cells to Unravel Cellular\u2019s Processes that Could Be Used to Establish Oocyte Quality Biomarkers with Clinical Application","volume":"30","author":"Grun","year":"2023","journal-title":"Reprod. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"84","DOI":"10.4103\/2096-2924.262387","article-title":"Expression of Target Genes in Cumulus Cells Derived from Human Oocytes with and without Blastocyst Formation","volume":"3","author":"Zhou","year":"2019","journal-title":"Reprod. Dev. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lemseffer, Y., Terret, M.E., Campillo, C., and Labrune, E. (2022). Methods for Assessing Oocyte Quality: A Review of Literature. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092184"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1071\/RD22217","article-title":"Non-invasive assessment of oocyte developmental competence","volume":"35","author":"Tan","year":"2022","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1093\/humrep\/dex309","article-title":"Age-related changes in the mitochondria of human mural granulosa cells","volume":"32","author":"Liu","year":"2017","journal-title":"Hum. Reprod."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1071\/RD06103","article-title":"Evaluation of oocyte quality: Morphological, cellular and molecular predictors","volume":"19","author":"Wang","year":"2007","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sirait, B., Wiweko, B., Jusuf, A.A., Iftitah, D., and Muharam, R. (2021). Oocyte Competence Biomarkers Associated with Oocyte Maturation: A Review. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.710292"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s13048-020-00696-7","article-title":"Transcriptomics of cumulus cells\u2014A window into oocyte maturation in humans","volume":"13","author":"Wyse","year":"2020","journal-title":"J. Ovarian Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1530\/rep.0.1220829","article-title":"Oocyte control of ovarian follicular development and function in mammals","volume":"122","author":"Eppig","year":"2001","journal-title":"Reproduction"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/humupd\/dmm040","article-title":"Oocyte-secreted factors: Regulators of cumulus cell function and oocyte quality","volume":"14","author":"Gilchrist","year":"2008","journal-title":"Hum. Reprod. Update"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1126\/science.1071965","article-title":"Intercellular communication in the mammalian ovary: Oocytes carry the conversation","volume":"296","author":"Matzuk","year":"2002","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/s43032-021-00505-6","article-title":"Reprogramming of glucose metabolism of cumulus cells and oocytes and its therapeutic significance","volume":"29","author":"Imanaka","year":"2022","journal-title":"Reprod. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"800739","DOI":"10.3389\/fphys.2021.800739","article-title":"Role of Granulosa Cells in the Aging Ovarian Landscape: A Focus on Mitochondrial and Metabolic Function","volume":"12","author":"Alberico","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1093\/humupd\/dmw028","article-title":"Ovarian ageing: The role of mitochondria in oocytes and follicles","volume":"22","author":"Boucret","year":"2016","journal-title":"Hum. Reprod. Update"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.1093\/humrep\/deab203","article-title":"Mitochondria-related changes and metabolic dysfunction in low prognosis patients under the POSEIDON classification","volume":"36","author":"Jiang","year":"2021","journal-title":"Hum. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.theriogenology.2022.04.004","article-title":"Spatiotemporal dynamics of SIRT 1, 2 and 3 during in vitro maturation of bovine oocytes","volume":"186","author":"Ferreira","year":"2022","journal-title":"Theriogenology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.theriogenology.2020.07.036","article-title":"Aging-related mitochondrial alterations in bovine oocytes","volume":"157","author":"Soares","year":"2020","journal-title":"Theriogenology"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sreerangaraja Urs, D.B., Wu, W.H., Komrskova, K., Postlerova, P., Lin, Y.F., Tzeng, C.R., and Kao, S.H. (2020). Mitochondrial Function in Modulating Human Granulosa Cell Steroidogenesis and Female Fertility. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103592"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1093\/humrep\/der140","article-title":"Evidence that carbonyl stress by methylglyoxal exposure induces DNA damage and spindle aberrations, affects mitochondrial integrity in mammalian oocytes and contributes to oocyte ageing","volume":"26","author":"Tatone","year":"2011","journal-title":"Hum. Reprod."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s10815-015-0621-0","article-title":"Mitochondrial DNA copy number in cumulus cells is a strong predictor of obtaining good-quality embryos after IVF","volume":"33","author":"Ogino","year":"2016","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/5584_2019_456","article-title":"Oocyte Aging: The Role of Cellular and Environmental Factors and Impact on Female Fertility","volume":"1247","author":"Ahmed","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Boitrelle, F., Shah, R., Saleh, R., Henkel, R., Kandil, H., Chung, E., Vogiatzi, P., Zini, A., Arafa, M., and Agarwal, A. (2021). The Sixth Edition of the WHO Manual for Human Semen Analysis: A Critical Review and SWOT Analysis. Life, 11.","DOI":"10.3390\/life11121368"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"ESHRE Special Interest Group of Embryology and Alpha Scientists in Reproductive Medicine (2017). The Vienna consensus: Report of an expert meeting on the development of art laboratory performance indicators. Hum. Reprod. Open, 2017, hox011.","DOI":"10.1093\/hropen\/hox011"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1007\/s43032-021-00532-3","article-title":"The Ratio of Mitochondrial DNA to Genomic DNA Copy Number in Cumulus Cell May Serve as a Biomarker of Embryo Quality in IVF Cycles","volume":"28","author":"Yang","year":"2021","journal-title":"Reprod. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"16778","DOI":"10.1038\/s41598-019-53066-9","article-title":"Application of extracellular flux analysis for determining mitochondrial function in mammalian oocytes and early embryos","volume":"9","author":"Muller","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100245","DOI":"10.1016\/j.xpro.2020.100245","article-title":"Measurement of mitochondrial respiration in adherent cells by Seahorse XF96 Cell Mito Stress Test","volume":"2","author":"Gu","year":"2021","journal-title":"STAR Protoc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1007\/s11427-022-2161-3","article-title":"The landscape of aging","volume":"65","author":"Cai","year":"2022","journal-title":"Sci. China Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"162","DOI":"10.18632\/aging.101381","article-title":"Mammalian oogenesis and female reproductive aging","volume":"10","author":"Duncan","year":"2018","journal-title":"Aging"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1093\/biolre\/ioab241","article-title":"Age-associated changes in cumulus cells and follicular fluid: The local oocyte microenvironment as a determinant of gamete quality","volume":"106","author":"Babayev","year":"2022","journal-title":"Biol. Reprod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4987436","DOI":"10.1155\/2016\/4987436","article-title":"How to Achieve High-Quality Oocytes? The Key Role of Myo-Inositol and Melatonin","volume":"2016","author":"Vitale","year":"2016","journal-title":"Int. J. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.bpobgyn.2006.09.004","article-title":"Ageing and ART: A waste of time and money?","volume":"21","author":"Ng","year":"2007","journal-title":"Best Pr. Res. Clin. Obs. Gynaecol."},{"key":"ref_36","first-page":"15","article-title":"Relation of cumulus cell status with single oocyte maturity, fertilization capability and patient age","volume":"15","author":"Sousa","year":"2014","journal-title":"J. Reprod. Infertil."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Tesarik, J., and Mendoza-Tesarik, R. (2023). Mitochondria in Human Fertility and Infertility. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108950"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"101168","DOI":"10.1016\/j.arr.2020.101168","article-title":"Mitochondria in Ovarian Aging and Reproductive Longevity","volume":"63","author":"Chiang","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15301","DOI":"10.1073\/pnas.1305462110","article-title":"Age-dependent dissociation of ATP synthase dimers and loss of inner-membrane cristae in mitochondria","volume":"110","author":"Daum","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.fertnstert.2022.04.019","article-title":"Mitochondrial dysfunction in cumulus cells is related to decreased reproductive capacity in advanced-age women","volume":"118","author":"Lu","year":"2022","journal-title":"Fertil. Steril."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.fertnstert.2022.06.024","article-title":"Cumulus cells mitochondrial dysfunction in advanced-age women","volume":"118","year":"2022","journal-title":"Fertil. Steril."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Richani, D., Poljak, A., Wang, B., Mahbub, S.B., Biazik, J., Campbell, J.M., Habibalahi, A., Stocker, W.A., Marinova, M.B., and Nixon, B. (2022). Oocyte and cumulus cell cooperativity and metabolic plasticity under the direction of oocyte paracrine factors. bioRxiv.","DOI":"10.1101\/2022.09.05.506599"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/mrd.22037","article-title":"A role for the Warburg effect in preimplantation embryo development: Metabolic modification to support rapid cell proliferation","volume":"79","author":"Krisher","year":"2012","journal-title":"Mol. Reprod. Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1016\/j.devcel.2021.07.020","article-title":"Metabolic plasticity drives development during mammalian embryogenesis","volume":"56","author":"Sharpley","year":"2021","journal-title":"Dev. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1177\/1933719115607996","article-title":"Expression Levels of the Oxidative Stress Response Gene ALDH3A2 in Granulosa-Lutein Cells Are Related to Female Age and Infertility Diagnosis","volume":"23","author":"Puopolo","year":"2016","journal-title":"Reprod. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.maturitas.2016.06.015","article-title":"Reproductive aging is associated with changes in oocyte mitochondrial dynamics, function, and mtDNA quantity","volume":"93","author":"Babayev","year":"2016","journal-title":"Maturitas"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/3\/281\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:05:19Z","timestamp":1760105119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/3\/281"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,26]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["biom14030281"],"URL":"https:\/\/doi.org\/10.3390\/biom14030281","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,26]]}}}