{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:23:40Z","timestamp":1790882620839,"version":"4.1.0"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"European Union\u2019s Horizon 2020 Research and Innovation Program"},{"name":"Marie Sk\u0142odowska-Curie","award":["860960"],"award-info":[{"award-number":["860960"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>Is there a relationship between the mitochondrial activity and the meiotic progression of oocytes from germinal vesicle (GV) to metaphase II (MII) stages in young and advanced maternal age (AMA) women?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>Poor mitochondrial metabolism impairs the meiotic progression of human GV oocytes, contributing to a lower oocyte maturation capacity of AMA oocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>AMA oocytes are characterized by diminished quality, mostly due to the higher rates of chromosomal segregation errors occurring during meiosis I. Another hallmark of AMA oocytes is impaired mitochondrial metabolism. Studies in mice have suggested a link between metabolic dysfunction and meiotic failure, but this relationship has not been fully elucidated in humans. Metabolic dynamics can be visualized by indirect measurements through mitochondrial staining and quantified more directly using fluorescence lifetime imaging microscopy (FLIM). This live-imaging approach can generate metabolic timelapse profiles of oocytes throughout meiosis. In the present study, we explored mitochondrial distribution and functionality in human oocytes at the GV and MII stages, obtained from young and AMA women, to establish the role of mitochondrial metabolism in meiosis progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                    <jats:p>A total of 340\u2009GV oocytes from young (\u226434\u2009years) and AMA (&amp;gt;37\u2009years) women were included in the study. Denuded GVs were matured in vitro in G2-plus medium for 30\u2009h. Maturation was determined by the presence of the extruded first polar body (PB1). The collected oocytes were processed for mitochondrial protein imaging (n\u2009=\u200980), or for live imaging (n\u2009=\u2009171). Moreover, 89 oocytes were used for loss-of-function analysis by treating young GVs with 1\u2009\u03bcM trifluoromethoxy-carbonylcyanide-phenylhydrazone (FCCP) for 30\u2009min before in vitro maturation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                    <jats:p>The proteins dihydrolipoamide-S-acetyltransferase (D-LAT) and translocase-of-outer mitochondrial-membrane (TOMM20) were analyzed in young and AMA oocytes by immunofluorescence to assess mitochondrial activity and localization, respectively. Fluorescence mean intensities (arbitrary-unit, AU) were quantified with ImageJ and compared by t-test; maturation rates were compared by chi-squared test. FLIM comprehensive metabolism (NAD(P)H; FAD+) was taken at GV stage. Different FLIM parameters (fluorescence intensity, fraction bound, short\/long lifetime) and the Redox ratio (NAD(P)H intensity\/FAD+ intensity) were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>The findings revealed that active mitochondria are specifically localized in the subcortical area, while mitochondria in general are distributed across the whole oocyte. This pattern was substantially maintained in AMA oocytes, which were in turn characterized by a lower mitochondrial activity (D-LAT intensity of 78\u00a0614\u2009\u00b1\u200958\u00a0534\u2009AU in young, 12\u00a0517\u2009\u00b1\u200910\u00a0187\u2009AU in AMA, P\u2009=\u20090.003), while a lower number of mitochondria was observed In AMA patients but the difference did not reach statistical significance (TOMM20 intensity of 61\u00a0674\u2009\u00b1\u200924\u00a0322\u2009AU in young, 32\u00a0186\u2009\u00b1\u200933\u00a0414\u2009AU in AMA, P\u2009=\u20090.195). Using non-invasive FLIM, we assessed the metabolic dynamics of maturing oocytes (Redox ratio in young 2e\u2009+\u200900\u2009\u00b1\u20090.15, in AMA 1e\u2009+\u200900\u2009\u00b1\u20090.16, P\u2009=\u20092.969e-05), confirming a similar pattern observed by immunofluorescence. Specifically, FLIM microscopy revealed that GV oocytes from young women slightly increased their metabolism, by 4% on average, after the GV breakdown, and the increase was very consistent across different oocytes. On the contrary, in AMA maturing oocytes, little to no increase in metabolism was observed; they were characterized instead by higher variability, and more AMA oocytes failed to successfully reach the MII stage [AMA oocytes (62.3%; 38\/61) compared with young oocytes (86.3%; 63\/73; P\u2009=\u20090.002). These differential trends observed in AMA oocytes compared to the young oocytes suggest that impaired metabolic activity significantly compromises maturation capacity, revealing a functional link between adequate metabolic levels and successful meiosis progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>Maturation rates were assessed by the presence of an extruded PB1 and variations in spindle assembly timings may have been overlooked. The quantification of mitochondrial activity in loss-of-function studies was assessed only by immunofluorescence staining. Additionally, the oocytes included in the present study were collected from women who underwent ovarian stimulation and may not faithfully recapitulate physiological maturation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>Our findings demonstrate the presence of a functional link between oocyte mitochondrial metabolism and meiosis progression, which may contribute to the decline of oocyte quality with aging. Overall, we provided evidence to understand the biological mechanisms in mitochondrial metabolism that might contribute to driving the decay in oocyte quality in AMA women.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                    <jats:p>This project received intramural funding from the Eugin Group and funding from the European Union\u2019s Horizon 2020 research and innovation program under the Marie Sk\u0142odowska-Curie grant agreement No 860960. T.S. is a former owner and former stock owner of Optiva Fertility Inc (company closed) and filed two patents for Optiva Fertility Inc (both abandoned). D.S.: Presenter EMD Senoro and Dep. Editor of Human Reproduction. All of the other authors (S.P., M.M., M.B., E.I., M.P., R.V., and F.Z.) have no conflicts of interest to declare. All of the authors contributed substantially to the manuscript and approve its submission.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION NUMBER<\/jats:title>\n                    <jats:p>N\/A.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/humrep\/deaf207","type":"journal-article","created":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T08:02:21Z","timestamp":1762675341000},"page":"2260-2271","source":"Crossref","is-referenced-by-count":5,"title":["Mitochondrial metabolism influences meiotic maturation in human oocytes of young and advanced maternal age women"],"prefix":"10.1093","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0300-7657","authenticated-orcid":false,"given":"Sara","family":"Pietroforte","sequence":"first","affiliation":[{"name":"Research and Development, Eugin Group , Barcelona,","place":["Spain"]},{"name":"Department of Cell Biology, Physiology and 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