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Disease\u2010specific induced pluripotent stem cells (iPSCs) model early developmental changes and cellular perturbations that are otherwise inaccessible from clinical settings. Here, we report the early changes in patient\u2010derived iPSCs carrying a homozygous recessive mutation, R741Q, in the <jats:italic>PLA2G6<\/jats:italic> gene. A gene\u2010edited R747W iPSC line mirrored these phenotypes, thus validating our initial findings. Bioenergetic dysfunction and hyperpolarization of mitochondrial membrane potentials were hallmarks of the PD iPSCs. Further, a concomitant increase in glycolytic activity indicated a possible compensation for mitochondrial respiration. Elevated basal reactive oxygen species (ROS) and decreased catalase expression were also observed in the disease iPSCs. No change in autophagy was detected. These inceptive changes could be potential targets for early intervention of prodromal PD in the absence of disease\u2010modifying therapies. However, additional investigations are crucial to delineate the cause\u2010effect relationships of these observations.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70059-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.70059","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T05:40:55Z","timestamp":1744004455000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Altered Mitochondrial Bioenergetics and Calcium Kinetics in Young\u2010Onset <i>PLA2G6<\/i> Parkinson's Disease <scp>iPSCs<\/scp>"],"prefix":"10.1111","volume":"169","author":[{"given":"Thasneem","family":"Musthafa","sequence":"first","affiliation":[{"name":"National Centre for Biological Sciences Tata Institute of Fundamental Research  Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Kavish","family":"Nizami","sequence":"additional","affiliation":[{"name":"National Centre for Biological Sciences Tata Institute of Fundamental Research  Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankita","family":"Mishra","sequence":"additional","affiliation":[{"name":"NKure Therapeutics Pvt Ltd Centre for Cellular and Molecular Platforms  Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaiti","family":"Hasan","sequence":"additional","affiliation":[{"name":"National Centre for Biological Sciences Tata Institute of Fundamental Research  Bangalore India"},{"name":"Centre for High Impact Neuroscience and Translational Applications  Kolkata India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3899-201X","authenticated-orcid":false,"given":"Renjitha","family":"Gopurappilly","sequence":"additional","affiliation":[{"name":"National Centre for Biological Sciences Tata Institute of Fundamental Research  Bangalore India"},{"name":"NKure Therapeutics Pvt Ltd Centre for Cellular and Molecular Platforms  Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2010.198"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.05.008"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21582"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.14670\/HH\u201012.25"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12242"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.9b00081"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010016\u20100303\u20107"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2005.03.002"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107044"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113544"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi020157z"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2014.09.070"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI129987"},{"key":"e_1_2_10_15_1","unstructured":"Chaudhry R. andM.Varacallo.2024.\u201cBiochemistry Glycolysis.\u201dIn: StatPearls [Internet]. 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