{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:27:14Z","timestamp":1793053634950,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:00:00Z","timestamp":1679011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Premature ovarian insufficiency (POI) is characterized by early loss of ovarian function before the age of 40\u00a0years. It is confirmed to have a strong and indispensable genetic component. Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) is a key inducer of mitochondrial protein quality control for the clearance of misfolded or damaged proteins, which is necessary to maintain mitochondrial function. Previous findings have shown that the variation in CLPP is closely related to the occurrence of POI, which is consistent with our findings. This study identified a novel CLPP missense variant (c.628G &amp;gt; A) in a woman with POI who presented with secondary amenorrhea, ovarian dysfunction, and primary infertility. The variant was located in exon 5 and resulted in a change from alanine to threonine (p.Ala210Thr). Importantly, Clpp was mainly localized in the cytoplasm of mouse ovarian granulosa cells and oocytes, and was relatively highly expressed in granulosa cells. Moreover, the overexpression of c.628G &amp;gt; A variant in human ovarian granulosa cells decreased the proliferative capacity. Functional experiments revealed that the inhibition of CLPP decreased the content and activity of oxidative respiratory chain complex IV by affecting the degradation of aggregated or misfolded COX5A, leading to the accumulation of reactive oxygen species and reduction of mitochondrial membrane potential, ultimately activating the intrinsic apoptotic pathways. The present study demonstrated that CLPP affected the apoptosis of granulosa cells, which might be one of the mechanisms by which CLPP aberrations led to the development of POI.<\/jats:p>","DOI":"10.3389\/fgene.2023.1141167","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:52:03Z","timestamp":1679014323000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["CLPP inhibition triggers apoptosis in human ovarian granulosa cells via COX5A abnormality\u2013Mediated mitochondrial dysfunction"],"prefix":"10.3389","volume":"14","author":[{"given":"Xiong","family":"Yuan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyi","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yugui","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danhua","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongrong","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods."},{"key":"B2","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.mito.2011.05.003","article-title":"The power of life--cytochrome c oxidase takes center stage in metabolic control, cell signalling and survival","volume":"12","author":"Arnold","year":"2012","journal-title":"Mitochondrion"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1038\/ncomms3139","article-title":"Landscape of the mitochondrial hsp90 metabolome in tumours","volume":"4","author":"Chae","year":"2013","journal-title":"Nat. Commun."},{"key":"B4","doi-asserted-by":"publisher","first-page":"672890","DOI":"10.3389\/fcell.2021.672890","article-title":"Premature ovarian insufficiency: Past, present, and future","volume":"9","author":"Chon","year":"2021","journal-title":"Front. Cell. Dev. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1016\/j.ccell.2015.05.004","article-title":"Inhibition of the mitochondrial protease ClpP as a therapeutic strategy for human acute myeloid leukemia","volume":"27","author":"Cole","year":"2015","journal-title":"Cancer Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/s0005-2728(00)00053-0","article-title":"Growth of the yeast Saccharomyces cerevisiae on a non-fermentable substrate: Control of energetic yield by the amount of mitochondria","volume":"1457","author":"Dejean","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"B7","doi-asserted-by":"publisher","first-page":"472","DOI":"10.4274\/jcrpe.2717","article-title":"A novel missense mutation in the CLPP gene causing Perrault syndrome type 3 in a Turkish family","volume":"8","author":"Dursun","year":"2016","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/antiox10010001","article-title":"Mitochondrial stress response gene clpp is not required for granulosa cell function","volume":"10","author":"Esencan","year":"2020","journal-title":"J. Artic. Antioxidants"},{"key":"B9","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1007\/s00439-021-02319-7","article-title":"New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder","volume":"141","author":"Faridi","year":"2022","journal-title":"Hum. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1038\/ncomms2397","article-title":"Human CLPP reverts the longevity phenotype of a fungal ClpP deletion strain","volume":"4","author":"Fischer","year":"2013","journal-title":"Nat. Commun."},{"key":"B11","doi-asserted-by":"publisher","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":"B12","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/j.bbrc.2018.12.071","article-title":"The regulation of Porphyromonas gingivalis biofilm formation by ClpP","volume":"509","author":"He","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B13","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1126\/science.7618105","article-title":"Simultaneous identification of bacterial virulence genes by negative selection","volume":"269","author":"Hensel","year":"1995","journal-title":"Science"},{"key":"B14","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1016\/j.ccell.2019.03.014","article-title":"Mitochondrial ClpP-mediated proteolysis induces selective cancer cell lethality","volume":"35","author":"Ishizawa","year":"2019","journal-title":"Cancer Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.ajhg.2013.02.013","article-title":"Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease","volume":"92","author":"Jenkinson","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s12868-020-00565-5","article-title":"COX5A over-expression protects cortical neurons from hypoxic ischemic injury in neonatal rats associated with TPI up-regulation","volume":"21","author":"Jiang","year":"2020","journal-title":"BMC Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.tem.2018.07.002","article-title":"Molecular genetics of premature ovarian insufficiency","volume":"29","author":"Jiao","year":"2018","journal-title":"Trends Endocrinol. Metab."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1038\/s12276-021-00665-0","article-title":"MicroRNA-26a\/b-5p promotes myocardial infarction-induced cell death by downregulating cytochrome c oxidase 5a","volume":"53","author":"Jung","year":"2021","journal-title":"Exp. Mol. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"35424","DOI":"10.1074\/jbc.M507240200","article-title":"Human mitochondrial ClpP is a stable heptamer that assembles into a tetradecamer in the presence of ClpX","volume":"280","author":"Kang","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1038\/s41591-022-02194-3","article-title":"Landscape of pathogenic mutations in premature ovarian insufficiency","volume":"29","author":"Ke","year":"2023","journal-title":"Nat. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"Hisat: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1038\/nprot.2009.86","article-title":"Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm","volume":"4","author":"Kumar","year":"2009","journal-title":"Nat. Protoc."},{"key":"B23","doi-asserted-by":"publisher","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":"B24","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1186\/1471-2105-12-323","article-title":"Rsem: Accurate transcript quantification from rna-seq data with or without a reference genome","volume":"12","author":"Li","year":"2011","journal-title":"BMC Bioinforma."},{"key":"B25","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1093\/bioinformatics\/btn025","article-title":"Soap: Short oligonucleotide alignment program","volume":"24","author":"Li","year":"2008","journal-title":"Bioinformatics"},{"key":"B26","doi-asserted-by":"publisher","first-page":"925012","DOI":"10.3389\/fpsyt.2022.925012","article-title":"Identification of molecular signatures associated with sleep disorder and Alzheimer's disease","volume":"13","author":"Liang","year":"2022","journal-title":"Front. Psychiatry."},{"key":"B27","doi-asserted-by":"publisher","first-page":"10049","DOI":"10.1096\/fj.201900179RR","article-title":"Timely expression and activation of YAP1 in granulosa cells is essential for ovarian follicle development","volume":"33","author":"Lv","year":"2019","journal-title":"Faseb J."},{"key":"B28","doi-asserted-by":"publisher","first-page":"102078","DOI":"10.1016\/j.cbpa.2021.07.003","article-title":"Substrates and interactors of the clpp protease in the mitochondria","volume":"66","author":"Mabanglo","year":"2022","journal-title":"Curr. Opin. Chem. Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1046\/j.1365-2958.1997.5911966.x","article-title":"Identification of Staphylococcus aureus virulence genes in a murine model of bacteraemia using signature-tagged mutagenesis","volume":"26","author":"Mei","year":"1997","journal-title":"Mol. Microbiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1385\/1-59745-275-0:87","article-title":"Protein identification by tandem mass spectrometry and sequence database searching","volume":"367","author":"Nesvizhskii","year":"2007","journal-title":"Methods Mol. Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"105803","DOI":"10.1016\/j.nbd.2022.105803","article-title":"Mitochondrial electron transport chain defects modify Parkinson's disease phenotypes in a drosophila model","volume":"171","author":"O'Hanlon","year":"2022","journal-title":"Neurobiol. Dis."},{"key":"B32","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/s41580-018-0092-0","article-title":"Mitochondrial proteins: From biogenesis to functional networks","volume":"20","author":"Pfanner","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1093\/humupd\/dmv036","article-title":"Genetics of primary ovarian insufficiency: New developments and opportunities","volume":"21","author":"Qin","year":"2015","journal-title":"Hum. Reprod. Update"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e52158","DOI":"10.7554\/eLife.52158","article-title":"A processive rotary mechanism couples substrate unfolding and proteolysis in the clpxp degradation machinery","volume":"9","author":"Ripstein","year":"2020","journal-title":"eLife"},{"key":"B35","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e1002507","DOI":"10.1371\/journal.pbio.1002507","article-title":"The mitochondrial unfoldase-peptidase complex ClpXP controls bioenergetics stress and metastasis","volume":"14","author":"Seo","year":"2016","journal-title":"PLoS. Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e36","DOI":"10.1002\/imt2.36","article-title":"Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform","volume":"1","author":"Shen","year":"2022","journal-title":"iMeta"},{"key":"B38","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nrm.2017.110","article-title":"The mitochondrial UPR: Mechanisms, physiological functions and implications in ageing","volume":"19","author":"Shpilka","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1038\/35072063","article-title":"The genetics and pathology of oxidative phosphorylation","volume":"2","author":"Smeitink","year":"2001","journal-title":"Nat. Rev. Genet."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2353","DOI":"10.1210\/en.2019-00441","article-title":"Mitochondrial dysfunction in primary ovarian insufficiency","volume":"160","author":"Tiosano","year":"2019","journal-title":"Endocrinology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1111\/cge.14127","article-title":"A novel homozygous variant in COX5A causes an attenuated phenotype with failure to thrive, lactic acidosis, hypoglycemia, and short stature","volume":"102","author":"Torraco","year":"2022","journal-title":"Clin. Genet."},{"key":"B42","doi-asserted-by":"publisher","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":"B43","doi-asserted-by":"publisher","first-page":"e89597","DOI":"10.1371\/journal.pone.0089597","article-title":"Impact of premature ovarian failure on mortality and morbidity among Chinese women","volume":"9","author":"Wu","year":"2014","journal-title":"PLoS One"},{"key":"B44","doi-asserted-by":"publisher","first-page":"215","DOI":"10.3389\/fnagi.2020.00215","article-title":"Cox5a plays a vital role in memory impairment associated with brain aging via the bdnf\/erk1\/2 signaling pathway","volume":"12","author":"Xiyang","year":"2020","journal-title":"Aging Neurosci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e21753","DOI":"10.1096\/fj.202100756R","article-title":"A kaleidoscopic view of ovarian genes associated with premature ovarian insufficiency and senescence","volume":"35","author":"Yang","year":"2021","journal-title":"Faseb J."},{"key":"B46","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1093\/humupd\/dmv037","article-title":"Cellular and molecular regulation of the activation of mammalian primordial follicles: Somatic cells initiate follicle activation in adulthood","volume":"21","author":"Zhang","year":"2015","journal-title":"Hum. Reprod. Update"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1141167\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:52:06Z","timestamp":1679014326000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1141167\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,17]]},"references-count":46,"alternative-id":["10.3389\/fgene.2023.1141167"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2023.1141167","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,17]]},"article-number":"1141167"}}