{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T13:26:51Z","timestamp":1771075611834,"version":"3.50.1"},"reference-count":25,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T00:00:00Z","timestamp":1705017600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sydney Partnership for Health Education Research and Enterprise (SPHERE)","award":["PF-15-014"],"award-info":[{"award-number":["PF-15-014"]}]},{"name":"National Breast Cancer Foundation Australia","award":["PF-15-014"],"award-info":[{"award-number":["PF-15-014"]}]},{"name":"Schizophrenia Research Institute, UNSW, Australia","award":["PF-15-014"],"award-info":[{"award-number":["PF-15-014"]}]},{"name":"Neuroscience Research Australia, NSW, Australia","award":["PF-15-014"],"award-info":[{"award-number":["PF-15-014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>\u2018Inner mitochondrial membrane peptidase 2 like\u2019 (IMMP2L) is a nuclear-encoded mitochondrial peptidase that has been conserved through evolutionary history, as has its target enzyme, \u2018mitochondrial glycerol phosphate dehydrogenase 2\u2032 (GPD2). IMMP2L is known to cleave the mitochondrial transit peptide from GPD2 and another nuclear-encoded mitochondrial respiratory-related protein, cytochrome C1 (CYC1). However, it is not known whether IMMP2L peptidase activates or alters the activity or respiratory-related functions of GPD2 or CYC1. Previous investigations found compelling evidence of behavioural change in the Immp2lKD\u2212\/\u2212 KO mouse, and in this study, EchoMRI analysis found that the organs of the Immp2lKD\u2212\/\u2212 KO mouse were smaller and that the KO mouse had significantly less lean mass and overall body weight compared with wildtype littermates (p &lt; 0.05). Moreover, all organs analysed from the Immp2lKD\u2212\/\u2212 KO had lower relative levels of mitochondrial reactive oxygen species (mitoROS). The kidneys of the Immp2lKD\u2212\/\u2212 KO mouse displayed the greatest decrease in mitoROS levels that were over 50% less compared with wildtype litter mates. Mitochondrial respiration was also lowest in the kidney of the Immp2lKD\u2212\/\u2212 KO mouse compared with other tissues when using succinate as the respiratory substrate, whereas respiration was similar to the wildtype when glutamate was used as the substrate. When glycerol-3-phosphate (G3P) was used as the substrate for Gpd2, we observed ~20% and ~7% respective decreases in respiration in female and male Immp2lKD\u2212\/\u2212 KO mice over time. Together, these findings indicate that the respiratory-related functions of mGpd2 and Cyc1 have been compromised to different degrees in different tissues and genders of the Immp2lKD\u2212\/\u2212 KO mouse. Structural analyses using AlphaFold2-Multimer further predicted that the interaction between Cyc1 and mitochondrial-encoded cytochrome b (Cyb) in Complex III had been altered, as had the homodimeric structure of the mGpd2 enzyme within the inner mitochondrial membrane of the Immp2lKD\u2212\/\u2212 KO mouse. mGpd2 functions as an integral component of the glycerol phosphate shuttle (GPS), which positively regulates both mitochondrial respiration and glycolysis. Interestingly, we found that nonmitochondrial respiration (NMR) was also dramatically lowered in the Immp2lKD\u2212\/\u2212 KO mouse. Primary mouse embryonic fibroblast (MEF) cell lines derived from the Immp2lKD\u2212\/\u2212 KO mouse displayed a ~27% decrease in total respiration, comprising a ~50% decrease in NMR and a ~12% decrease in total mitochondrial respiration, where the latter was consistent with the cumulative decreases in substrate-specific mediated mitochondrial respiration reported here. This study is the first to report the role of Immp2l in enhancing Gpd2 structure and function, mitochondrial respiration, nonmitochondrial respiration, organ size and homeostasis.<\/jats:p>","DOI":"10.3390\/ijms25020990","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T11:43:53Z","timestamp":1705059833000},"page":"990","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Immp2l Enhances the Structure and Function of Mitochondrial Gpd2 Dehydrogenase"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7196-9623","authenticated-orcid":false,"given":"Raymond A.","family":"Clarke","sequence":"first","affiliation":[{"name":"Discipline of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Ingham Institute for Applied Medical Research, Sydney, NSW 2170, Australia"},{"name":"Academic Unit of Infant Child and Adolescent Services (AUCS), South Western Sydney Local Health District, Liverpool, NSW 2170, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hemna","family":"Govindaraju","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Biomedical Sciences, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Beretta","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen","family":"Olzomer","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam J.","family":"Lawther","sequence":"additional","affiliation":[{"name":"Laboratory of ImmunoPsychiatry, Neuroscience Research Australia, Randwick, NSW 2031, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3772-5745","authenticated-orcid":false,"given":"Adam K.","family":"Walker","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Laboratory of ImmunoPsychiatry, Neuroscience Research Australia, Randwick, NSW 2031, Australia"},{"name":"Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiming","family":"Fang","sequence":"additional","affiliation":[{"name":"Ingham Institute for Applied Medical Research, Sydney, NSW 2170, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6296-8306","authenticated-orcid":false,"given":"Valsamma","family":"Eapen","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Ingham Institute for Applied Medical Research, Sydney, NSW 2170, Australia"},{"name":"Academic Unit of Infant Child and Adolescent Services (AUCS), South Western Sydney Local Health District, Liverpool, NSW 2170, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8777-3054","authenticated-orcid":false,"given":"Tzipi Cohen","family":"Hyams","sequence":"additional","affiliation":[{"name":"Ingham Institute for Applied Medical Research, Sydney, NSW 2170, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6125-1183","authenticated-orcid":false,"given":"Murray","family":"Killingsworth","sequence":"additional","affiliation":[{"name":"Ingham Institute for Applied Medical Research, Sydney, NSW 2170, Australia"},{"name":"NSW Health Pathology, Liverpool Hospital Campus, Liverpool, NSW 2107, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8577-3536","authenticated-orcid":false,"given":"Wallace","family":"Bridge","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nigel","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Biomedical Sciences, University of New South Wales, Sydney, NSW 2052, 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Biophys. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.1073\/pnas.0712331105","article-title":"Structure of glycerol-3-phosphate dehydrogenase, an essential monotopic membrane enzyme involved in respiration and metabolism","volume":"105","author":"Yeh","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lawther, A.J., Zieba, J., Fang, Z., Furlong, T.M., Conn, I., Govindaraju, H., Choong, L.L.Y., Turner, N., Siddiqui, K.S., and Bridge, W. (2023). Antioxidant Behavioural Phenotype in the Immp2l Gene Knock-Out Mouse. Genes, 14.","DOI":"10.3390\/genes14091717"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1095\/biolreprod.107.065987","article-title":"A mutation in the inner mitochondrial membrane peptidase 2-like gene (immp2l) affects mitochondrial function and impairs fertility in mice","volume":"78","author":"Lu","year":"2008","journal-title":"Biol. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1007\/s11596-023-2726-5","article-title":"Immp2l Mutation Induces Mitochondrial Membrane Depolarization and Complex III Activity Suppression after Middle Cerebral Artery Occlusion in Mice","volume":"43","author":"Ma","year":"2023","journal-title":"Curr. Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1007\/s11064-017-2207-y","article-title":"Suppression of Inner Mitochondrial Membrane Peptidase 2-Like (IMMP2L) Gene Exacerbates Hypoxia-Induced Neural Death Under High Glucose Condition","volume":"42","author":"Ma","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.redox.2014.08.006","article-title":"Examination of bioenergetic function in the inner mitochondrial membrane peptidase 2-like (Immp2l) mutant mice","volume":"2","author":"Bharadwaj","year":"2014","journal-title":"Redox Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/s41422-018-0043-5","article-title":"Switching off IMMP2L signaling drives senescence via simultaneous metabolic alteration and blockage of cell death","volume":"28","author":"Yuan","year":"2018","journal-title":"Cell Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/j.1474-9726.2011.00686.x","article-title":"Mitochondrial peptidase IMMP2L mutation causes early onset of age-associated disorders and impairs adult stem cell self-renewal","volume":"10","author":"George","year":"2011","journal-title":"Aging Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/acel.12426","article-title":"The immp2l mutation causes age-dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment","volume":"15","author":"Liu","year":"2016","journal-title":"Aging Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1016\/j.freeradbiomed.2012.04.003","article-title":"Oxidative stress is involved in age-dependent spermatogenic damage of Immp2l mutant mice","volume":"52","author":"George","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1089\/dna.1998.17.301","article-title":"Rat mitochondrial glycerol-3-phosphate dehydrogenase gene: Multiple promoters, high levels in brown adipose tissue, and tissue-specific regulation by thyroid hormone","volume":"17","author":"Gong","year":"1998","journal-title":"DNA Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41592-022-01488-1","article-title":"ColabFold: Making protein folding accessible to all","volume":"19","author":"Mirdita","year":"2022","journal-title":"Nat. Methods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"W404","DOI":"10.1093\/nar\/gkad350","article-title":"PAE viewer: A webserver for the interactive visualization of the predicted aligned error for multimer structure predictions and crosslinks","volume":"51","author":"Elfmann","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure visualization for researchers, educators, and developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112057","DOI":"10.1016\/j.bbr.2019.112057","article-title":"First behavioural assessment of a novel Immp2l knockdown mouse model with relevance for Gilles de la Tourette syndrome and Autism spectrum disorder","volume":"374","author":"Kreilaus","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114610","DOI":"10.1016\/j.bbr.2023.114610","article-title":"Immp2l knockdown in male mice increases stimulus-driven instrumental behaviour but does not alter goal-directed learning or neuron density in cortico-striatal circuits in a model of Tourette syndrome and autism spectrum disorder","volume":"452","author":"Leung","year":"2023","journal-title":"Behav. Brain Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5087","DOI":"10.1038\/s41598-019-41572-9","article-title":"Measurement of lactate levels in postmortem brain, iPSCs, and animal models of schizophrenia","volume":"9","author":"Sullivan","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/sj.cdd.4402307","article-title":"Mitochondrial complex III regulates hypoxic activation of HIF","volume":"15","author":"Klimova","year":"2008","journal-title":"Cell Death Differ."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4089","DOI":"10.1111\/j.1742-4658.2010.07804.x","article-title":"Evidence for the slow reaction of hypoxia-inducible factor prolyl hydroxylase 2 with oxygen","volume":"277","author":"Flashman","year":"2010","journal-title":"FEBS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1016\/j.bbrc.2018.07.047","article-title":"Protein hypoacylation induced by Sirt5 overexpression has minimal metabolic effect in mice","volume":"503","author":"Bentley","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12264","DOI":"10.1096\/fj.201900234R","article-title":"Regulation of mitochondrial metabolism in murine skeletal muscle by the medium-chain fatty acid receptor Gpr84","volume":"33","author":"Montgomery","year":"2019","journal-title":"FASEB J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.1194\/jlr.M040451","article-title":"Contrasting metabolic effects of medium-versus long-chain fatty acids in skeletal muscle","volume":"54","author":"Montgomery","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e104073","DOI":"10.15252\/embj.2019104073","article-title":"A novel approach to measure mitochondrial respiration in frozen biological samples","volume":"39","author":"Benador","year":"2020","journal-title":"EMBO J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/nprot.2006.478","article-title":"Organelle isolation: Functional mitochondria from mouse liver, muscle and cultured filroblasts","volume":"2","author":"Frezza","year":"2007","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/2\/990\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:45:55Z","timestamp":1760103955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/2\/990"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,12]]},"references-count":25,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ijms25020990"],"URL":"https:\/\/doi.org\/10.3390\/ijms25020990","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,12]]}}}