{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T23:05:21Z","timestamp":1790895921292,"version":"4.1.0"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"European Research Council","award":["714472"],"award-info":[{"award-number":["714472"]}]},{"name":"French National Center for Scientific Research"},{"name":"AMMI"},{"name":"Tunisian Ministry of High Education and Scientific Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pyruvate is an essential metabolite produced by glycolysis in the cytosol and must be transported across the inner mitochondrial membrane into the mitochondrial matrix, where it is oxidized to fuel mitochondrial respiration. Pyruvate import is performed by the mitochondrial pyruvate carrier (MPC), a hetero-oligomeric complex composed by interdependent subunits MPC1 and MPC2. Pathogenic variants in the MPC1 gene disrupt mitochondrial pyruvate uptake and oxidation and cause autosomal-recessive early-onset neurological dysfunction in humans. The present work describes the first pathogenic variants in MPC2 associated with human disease in four patients from two unrelated families. In the first family, patients presented with antenatal developmental abnormalities and harboured a homozygous c.148T&amp;gt;C (p.Trp50Arg) variant. In the second family, patients that presented with infantile encephalopathy carried a missense c.2T&amp;gt;G (p.Met1?) variant disrupting the initiation codon. Patient-derived skin fibroblasts exhibit decreased pyruvate-driven oxygen consumption rates with normal activities of the pyruvate dehydrogenase complex and mitochondrial respiratory chain and no defects in mitochondrial content or morphology. Re-expression of wild-type MPC2 restored pyruvate-dependent respiration rates in patient-derived fibroblasts.<\/jats:p><jats:p>The discovery of pathogenic variants in MPC2 therefore broadens the clinical and genetic landscape associated with inborn errors in pyruvate metabolism.<\/jats:p>","DOI":"10.1093\/brain\/awac444","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T15:17:09Z","timestamp":1669043829000},"page":"858-864","source":"Crossref","is-referenced-by-count":18,"title":["<i>MPC2<\/i>variants disrupt mitochondrial pyruvate metabolism and cause an early-onset mitochondriopathy"],"prefix":"10.1093","volume":"146","author":[{"given":"Claire","family":"Pujol","sequence":"first","affiliation":[{"name":"Mitochondrial Biology Group, Institut Pasteur, CNRS UMR 3691 , 75015 Paris , France"},{"name":"Universit\u00e9 Paris Cit\u00e9 , 75006 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Lebigot","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Bic\u00eatre Hospital, APHP Paris Saclay , 94270 Le Kremlin Bic\u00eatre , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Gaignard","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Bic\u00eatre Hospital, APHP Paris Saclay , 94270 Le Kremlin Bic\u00eatre , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Said","family":"Galai","sequence":"additional","affiliation":[{"name":"Research Laboratory of Neurological Diseases of the Child (LR18SP04), Department of Clinical Biology, Faculty of Medicine of Tunis, National Institute Mongi Ben Hmida of Neurology, University of Tunis El Manar , 1068 Tunis , Tunisia"},{"name":"Research Laboratory of Neurological Diseases of the Child (LR18SP04), Department of Pediatric Neurology, National Institute Mongi Ben Hmida of Neurology, Faculty of Medicine of Tunis, University of Tunis El Manar , 1068 Tunis , Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichraf","family":"Kraoua","sequence":"additional","affiliation":[{"name":"Research Laboratory of Neurological Diseases of the Child (LR18SP04), Department of Pediatric Neurology, National Institute Mongi Ben Hmida of Neurology, Faculty of Medicine of Tunis, University of Tunis El Manar , 1068 Tunis , Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Bault","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Poissy\u2014Saint Germain en Laye Hospital , 78300 Poissy , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolphe","family":"Dard","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Poissy\u2014Saint Germain en Laye Hospital , 78300 Poissy , France"},{"name":"Department of Medical Genetics, Poissy\u2014Saint Germain en Laye Hospital , 78300 Poissy , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilhem Ben","family":"Youssef-Turki","sequence":"additional","affiliation":[{"name":"Research Laboratory of Neurological Diseases of the Child (LR18SP04), Department of Pediatric Neurology, National Institute Mongi Ben Hmida of Neurology, Faculty of Medicine of Tunis, University of Tunis El Manar , 1068 Tunis , Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souheil","family":"Omar","sequence":"additional","affiliation":[{"name":"Research Laboratory of Neurological Diseases of the Child (LR18SP04), Department of Clinical Biology, Faculty of Medicine of Tunis, National Institute Mongi Ben Hmida of Neurology, University of Tunis El Manar , 1068 Tunis , Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Boutron","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Bic\u00eatre Hospital, APHP Paris Saclay , 94270 Le Kremlin Bic\u00eatre , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6770-6222","authenticated-orcid":false,"given":"Timothy","family":"Wai","sequence":"additional","affiliation":[{"name":"Mitochondrial Biology Group, Institut Pasteur, CNRS UMR 3691 , 75015 Paris , France"},{"name":"Universit\u00e9 Paris Cit\u00e9 , 75006 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelhamid","family":"Slama","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Bic\u00eatre Hospital, APHP Paris Saclay , 94270 Le Kremlin Bic\u00eatre , France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s00401-013-1115-8","article-title":"Hereditary spastic paraplegia: Clinico-pathologic features and emerging molecular mechanisms","volume":"126","author":"Fink","year":"2013","journal-title":"Acta Neuropathol"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1042\/bj1720389","article-title":"Stimulation of pyruvate transport in metabolizing mitochondria through changes in the transmembrane pH gradient induced by glucagon treatment of rats","volume":"172","author":"Halestrap","year":"1978","journal-title":"Biochem J"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1432-1033.1974.tb03831.x","article-title":"On the mechanism of translocation of pyruvate and other monocarboxylic acids in rat-liver mitochondria","volume":"49","author":"Papa","year":"1974","journal-title":"Eur J Biochem"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/S1096-7192(03)00016-7","article-title":"Impaired mitochondrial pyruvate importation in a patient and a fetus at risk","volume":"78","author":"Brivet","year":"2003","journal-title":"Mol Genet Metab"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1126\/science.1218099","article-title":"A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, drosophila, and humans","volume":"337","author":"Bricker","year":"2012","journal-title":"Science"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1126\/science.1218530","article-title":"Identification and functional expression of the mitochondrial pyruvate carrier","volume":"337","author":"Herzig","year":"2012","journal-title":"Science"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.3390\/biom10071068","article-title":"The multifaceted pyruvate metabolism: Role of the mitochondrial pyruvate carrier","volume":"10","author":"Zangari","year":"2020","journal-title":"Biomolecules"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.molcel.2014.09.026","article-title":"A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth","volume":"56","author":"Schell","year":"2014","journal-title":"Mol Cell"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2021\/6618837","article-title":"Decreased expression of MPC2 contributes to aerobic glycolysis and colorectal cancer proliferation by activating mTOR pathway","volume":"2021","author":"Kuerbanjiang","year":"2021","journal-title":"J Immunol Res"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1038\/s42255-020-00276-5","article-title":"Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy","volume":"2","author":"Fernandez-Caggiano","year":"2020","journal-title":"Nat Metab"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1038\/s41418-020-00729-0","article-title":"Heart failure\u2014Emerging roles for the mitochondrial pyruvate carrier","volume":"28","author":"Fernandez-Caggiano","year":"2021","journal-title":"Cell Death Differ"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1186\/s12882-020-01931-5","article-title":"Mitochondrial pyruvate carrier: A potential target for diabetic nephropathy","volume":"21","author":"Zhu","year":"2020","journal-title":"BMC Nephrol"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/s42255-020-00288-1","article-title":"Mitochondrial pyruvate carriers are required for myocardial stress adaptation","volume":"2","author":"Zhang","year":"2020","journal-title":"Nat Metab"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1002\/jimd.12462","article-title":"Identification and characterization of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency","volume":"45","author":"Jiang","year":"2022","journal-title":"J Inher Metab Dis"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"e126132","DOI":"10.1172\/jci.insight.126132","article-title":"Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction","volume":"4","author":"Oonthonpan","year":"2019","journal-title":"JCI Insight"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.ajhg.2010.02.004","article-title":"Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly\u2013hydrocephaly syndrome (Fowler syndrome)","volume":"86","author":"Meyer","year":"2010","journal-title":"Am J Hum Genet"},{"key":"2023030117464743600_","volume-title":"Genereviews\u00ae","author":"Ganetzky","year":"1993"},{"key":"2023030117464743600_","volume-title":"Genereviews\u00ae","author":"Wang","year":"1993"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1016\/j.celrep.2014.05.017","article-title":"Mitochondrial pyruvate carrier 2 hypomorphism in mice leads to defects in glucose-stimulated insulin secretion","volume":"7","author":"Vigueira","year":"2014","journal-title":"Cell Rep"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/j.devcel.2021.02.009","article-title":"Quality control of the mitochondrion","volume":"56","author":"Ng","year":"2021","journal-title":"Dev Cell"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1038\/emboj.2011.477","article-title":"Nonsense mutations in the COX1 subunit impair the stability of respiratory chain complexes rather than their assembly: Turnover of mitochondrial proteins","volume":"31","author":"Hornig-Do","year":"2012","journal-title":"EMBO J"},{"key":"2023030117464743600_","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1093\/brain\/awab303","article-title":"CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis","volume":"145","author":"Rumyantseva","year":"2022","journal-title":"Brain"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awac444\/48541480\/awac444.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/146\/3\/858\/49356287\/awac444.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/146\/3\/858\/49356287\/awac444.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T08:29:46Z","timestamp":1678696186000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/146\/3\/858\/6843624"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,23]]},"references-count":22,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,11,23]]},"published-print":{"date-parts":[[2023,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awac444","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,3,1]]},"published":{"date-parts":[[2022,11,23]]}}}