{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T06:25:33Z","timestamp":1790576733270,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T00:00:00Z","timestamp":1706918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Foundation for Embryonic Competence to E.S"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondrial unfolded protein stress response (mtUPR) plays a critical role in regulating cellular and metabolic stress response and helps maintain protein homeostasis. Caseinolytic peptidase P (CLPP) is one of the key regulators of mtUPR and promotes unfolded protein degradation. Previous studies demonstrated that global deletion of Clpp resulted in female infertility, whereas no impairment was found in the mouse model with targeted deletion of Clpp in cumulus\/granulosa cells. These results suggest the need to delineate the function of Clpp in oocytes. In this study, we aimed to further explore the role of mtUPR in female reproductive competence and senescence using a mouse model. Oocyte-specific targeted deletion of Clpp in mice resulted in female subfertility associated with metabolic and functional abnormalities in oocytes, thus highlighting the importance of CLPP-mediated protein homeostasis in oocyte competence and reproductive function.<\/jats:p>","DOI":"10.3390\/ijms25031866","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T05:22:44Z","timestamp":1707110564000},"page":"1866","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility"],"prefix":"10.3390","volume":"25","author":[{"given":"Yagmur","family":"Ergun","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"IVIRMA Global Research Alliance, IVIRMA New Jersey, Marlton, NJ 07920, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysegul Gizem","family":"Imamoglu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5929-2357","authenticated-orcid":false,"given":"Mauro","family":"Cozzolino","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"IVIRMA Global Research Alliance, IVI Roma, 00169 Rome, Italy"},{"name":"IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigaci\u00f3n Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7073-2819","authenticated-orcid":false,"given":"Cem","family":"Demirkiran","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7766-409X","authenticated-orcid":false,"given":"Murat","family":"Basar","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale Fertility Center, Orange, CT 06477, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akanksha","family":"Garg","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2BX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2550-6396","authenticated-orcid":false,"given":"Raziye Melike","family":"Yildirim","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emre","family":"Seli","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale Fertility Center, Orange, CT 06477, USA"},{"name":"IVIRMA Global Research Alliance, IVIRMA New Jersey, Basking Ridge, NJ 07920, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.mito.2010.09.012","article-title":"Mitochondrial function in the human oocyte and embryo and their role in developmental competence","volume":"11","year":"2011","journal-title":"Mitochondrion"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1055\/s-0035-1567821","article-title":"Mitochondrial DNA Assessment to Determine Oocyte and Embryo Viability","volume":"33","author":"Fragouli","year":"2015","journal-title":"Semin. Reprod. Med."},{"key":"ref_3","first-page":"hoy023","article-title":"Bernabeu, Comprehensive mitochondrial DNA analysis and IVF outcome","volume":"2018","author":"BLledo","year":"2018","journal-title":"Hum. Reprod. Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1093\/molehr\/7.5.425","article-title":"Mitochondrial DNA content affects the fertilizability of human oocytes","volume":"7","author":"Reynier","year":"2001","journal-title":"Mol. Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1002\/aja.1001710309","article-title":"Mitochondrial reorganization during resumption of arrested meiosis in the mouse oocyte","volume":"171","author":"Runner","year":"1984","journal-title":"Am. J. Anat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1620\/tjem.210.137","article-title":"Correlation of Abnormal Mitochondrial Distribution in Mouse Oocytes with Reduced Developmental Competence","volume":"210","author":"Nagai","year":"2006","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1534\/genetics.106.061580","article-title":"Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response","volume":"174","author":"Benedetti","year":"2006","journal-title":"Genetics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.1093\/emboj\/cdf445","article-title":"A mitochondrial specific stress response in mammalian cells","volume":"21","author":"Zhao","year":"2002","journal-title":"Embo J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.molcel.2015.02.008","article-title":"Mitochondrial and Nuclear Accumulation of the Transcription Factor ATFS-1 Promotes OXPHOS Recovery during the UPRmt","volume":"58","author":"Nargund","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.devcel.2007.07.016","article-title":"ClpP Mediates Activation of a Mitochondrial Unfolded Protein Response in C. elegans","volume":"13","author":"Haynes","year":"2007","journal-title":"Dev. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12862","DOI":"10.1038\/s41598-018-30311-1","article-title":"Perrault syndrome type 3 caused by diverse molecular defects in CLPP","volume":"8","author":"Brodie","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Key, J., Gispert, S., Koornneef, L., Sleddens-Linkels, E., Kohli, A., Torres-Odio, S., Koepf, G., Amr, S., Reichlmeir, M., and Harter, P.N. (2022). CLPP Depletion Causes Diplotene Arrest; Underlying Testis Mitochondrial Dysfunction Occurs with Accumulation of Perrault Proteins ERAL1, PEO1, and HARS2. Cells, 12.","DOI":"10.3390\/cells12010052"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/ajmg.a.20616","article-title":"Perrault syndrome: Evidence for progressive nervous system involvement","volume":"128A","author":"Fiumara","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e12784","DOI":"10.1111\/acel.12784","article-title":"Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre-implantation embryos","volume":"17","author":"Wang","year":"2018","journal-title":"Aging Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4871","DOI":"10.1093\/hmg\/ddt338","article-title":"Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors","volume":"22","author":"Gispert","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Esencan, E., Cozzolino, M., Imamoglu, G., and Seli, E. (2020). Mitochondrial Stress Response Gene Clpp Is Not Required for Granulosa Cell Function. Antioxidants, 10.","DOI":"10.3390\/antiox10010001"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1122012","DOI":"10.3389\/fendo.2023.1122012","article-title":"Mitochondrial stress response gene Clpp deficiency impairs oocyte competence and deteriorate cyclophosphamide-induced ovarian damage in young mice","volume":"14","author":"Li","year":"2023","journal-title":"Front. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<110::AID-GENE2>3.0.CO;2-8","article-title":"Expression of Cre recombinase in mouse oocytes: A means to study maternal effect genes","volume":"26","author":"Binns","year":"2000","journal-title":"Genesis"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ren, Y., Suzuki, H., Jagarlamudi, K., Golnoski, K., McGuire, M., Lopes, R., Pachnis, V., and Rajkovic, A. (2015). Lhx8 regulates primordial follicle activation and postnatal folliculogenesis. BMC Biol., 13.","DOI":"10.1186\/s12915-015-0151-3"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbabio.2009.07.013","article-title":"Emerging roles of mitochondrial proteases in neurodegeneration","volume":"1797","author":"Martinelli","year":"2010","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sheng, X., Liu, C., Yan, G., Li, G., Liu, J., Yang, Y., Li, S., Li, Z., Zhou, J., and Zhen, X. (2022). The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals. eBioMedicine, 75.","DOI":"10.1016\/j.ebiom.2021.103790"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41389-021-00306-1","article-title":"LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival","volume":"10","author":"Lee","year":"2021","journal-title":"Oncogenesis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0303-7207(99)00236-1","article-title":"The mouse zona pellucida: Folliculogenesis, fertility and pre-implantation development","volume":"163","author":"Rankin","year":"2000","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"648","DOI":"10.21451\/1984-3143-AR2018-0019","article-title":"Control of growth and development of preantral follicle: Insights from in vitro culture","volume":"15","author":"Silva","year":"2018","journal-title":"Anim. Reprod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"bqaa001","DOI":"10.1210\/endocr\/bqaa001","article-title":"Mitochondrial Dysfunction and Ovarian Aging","volume":"161","author":"Kasapoglu","year":"2020","journal-title":"Endocrinology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/s41419-019-1799-3","article-title":"Mitofusin 1 is required for female fertility and to maintain ovarian follicular reserve","volume":"10","author":"Zhang","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.18632\/aging.102024","article-title":"Mitofusin 2 plays a role in oocyte and follicle development, and is required to maintain ovarian follicular reserve during reproductive aging","volume":"11","author":"Zhang","year":"2019","journal-title":"Aging"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1111\/acel.12368","article-title":"Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging","volume":"14","author":"Burstein","year":"2015","journal-title":"Aging Cell"},{"key":"ref_29","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_30","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.biocel.2014.08.011","article-title":"Mitochondria: Participation to infertility as source of energy and cause of senescence","volume":"55","author":"Benkhalifa","year":"2014","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.placenta.2013.03.013","article-title":"Low expression of Mfn2 is associated with mitochondrial damage and apoptosis in the placental villi of early unexplained miscarriage","volume":"34","author":"Pang","year":"2013","journal-title":"Placenta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1177\/147323001204000238","article-title":"Adenosine triphosphate content in human unfertilized oocytes, undivided zygotes and embryos unsuitable for transfer or cryopreservation","volume":"40","author":"Zhao","year":"2012","journal-title":"J. Int. Med. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"123","DOI":"10.5534\/wjmh.2014.32.3.123","article-title":"Understanding the role of heat shock protein isoforms in male fertility, aging and apoptosis","volume":"32","author":"Purandhar","year":"2014","journal-title":"World J. Men\u2019s Health"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jee, B., Dhar, R., Singh, S., and Karmakar, S. (2021). Heat Shock Proteins and Their Role in Pregnancy: Redefining the Function of \u201cOld Rum in a New Bottle\u201d. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.648463"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S108","DOI":"10.1016\/S0015-0282(02)03664-6","article-title":"Are heat shock proteins acting as modulators of pre-implantation mouse embryo development and apoptosis?","volume":"78","author":"Esfandiari","year":"2002","journal-title":"Fertil. Steril."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Salmeri, N., Vigan\u00f2, P., Cavoretto, P., Marci, R., and Candiani, M. (Rev. Endocr. Metab. Disord., 2023). The kisspeptin system in and beyond reproduction: Exploring intricate pathways and potential links between endometriosis and polycystic ovary syndrome, Rev. Endocr. Metab. Disord., ahead of print.","DOI":"10.1007\/s11154-023-09826-0"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.fertnstert.2012.02.021","article-title":"Analysis of the expression of neurokinin B, kisspeptin, and their cognate receptors NK3R and KISS1R in the human female genital tract","volume":"97","author":"Pinto","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"29073","DOI":"10.1038\/srep29073","article-title":"Beyond the brain-Peripheral kisspeptin signaling is essential for promoting endometrial gland development and function","volume":"6","author":"Fernandois","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Mattam, U., Talari, N.K., Paripati, A.K., Krishnamoorthy, T., and Sepuri, N.B.V. (2021). Kisspeptin preserves mitochondrial function by inducing mitophagy and autophagy in aging rat brain hippocampus and human neuronal cell line. Biochim. Biophys. Acta Mol. Cell Res., 1868.","DOI":"10.1016\/j.bbamcr.2020.118852"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1093\/humupd\/dmy046","article-title":"Potential roles for the kisspeptin\/kisspeptin receptor system in implantation and placentation","volume":"25","author":"Hu","year":"2019","journal-title":"Hum. Reprod. Update"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Evans, M.C., Lord, R.A., and Anderson, G.M. (2021). Multiple Leptin Signalling Pathways in the Control of Metabolism and Fertility: A Means to Different Ends?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179210"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/372425a0","article-title":"Positional cloning of the mouse obese gene and its human homologue","volume":"372","author":"Zhang","year":"1994","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1210\/endo.138.3.5024","article-title":"Leptin treatment rescues the sterility of genetically obese ob\/ob males","volume":"138","author":"Mounzih","year":"1997","journal-title":"Endocrinology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4667","DOI":"10.1172\/JCI67615","article-title":"Leptin regulation of Hsp60 impacts hypothalamic insulin signaling","volume":"123","author":"Kleinridders","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"101276","DOI":"10.1016\/j.molmet.2021.101276","article-title":"HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue","volume":"53","author":"Hauffe","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1073\/pnas.0408378102","article-title":"An embryonic poly(A)-binding protein (ePAB) is expressed in mouse oocytes and early preimplantation embryos","volume":"102","author":"Seli","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"(2016). Pascale May-Panloup, Lisa Boucret, Juan-Manuel Chao de la Barca, Val\u00e9rie Desquiret-Dumas, V\u00e9ronique Ferr\u00e9-L\u2019Hotellier, Catherine Morini\u00e8re, Philippe Descamps, Vincent Procaccio, Pascal Reynier, Ovarian ageing: The role of mitochondria in oocytes and follicles. Hum. Reprod. Update, 22, 725\u2013743.","DOI":"10.1093\/humupd\/dmw028"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1007\/s43032-022-01014-w","article-title":"Targeted Deletion of Mitofusin 1 and Mitofusin 2 Causes Female Infertility and Loss of Follicular Reserve","volume":"30","author":"Cozzolino","year":"2022","journal-title":"Reprod. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/3\/1866\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:54:25Z","timestamp":1760104465000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/3\/1866"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,3]]},"references-count":48,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["ijms25031866"],"URL":"https:\/\/doi.org\/10.3390\/ijms25031866","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,3]]}}}