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The mitochondrial pyruvate carrier (MPC) plays a vital role in transporting pyruvate from the cytosol into the organelle. In humans, MPC is a hetero\u2010oligomeric complex formed by the <jats:italic>MPC1<\/jats:italic> and <jats:italic>MPC2<\/jats:italic> paralogs that are both necessary to stabilize each other and form a functional MPC. MPC deficiency (OMIM#614741) due to pathogenic <jats:italic>MPC1<\/jats:italic> variants is a rare autosomal recessive disease involving developmental delay, microcephaly, growth failure, and increased serum lactate and pyruvate. To date, two <jats:italic>MPC1<\/jats:italic> variants in four cases have been reported, though only one with a detailed clinical description. Herein, we report three novel pathogenic <jats:italic>MPC1<\/jats:italic> variants in six patients from three unrelated families, identified within European, Kuwaiti, and Chinese mitochondrial disease patient cohorts, one of whom presented as a Leigh\u2010like syndrome. Functional analysis in primary fibroblasts from the patients revealed decreased expression of MPC1 and MPC2. We rescued pyruvate\u2010driven oxygen consumption rate in patient's fibroblasts by reconstituting with wild\u2010type <jats:italic>MPC1<\/jats:italic>. Complementing homozygous <jats:italic>MPC1<\/jats:italic> mutant cDNA with CRISPR\u2010deleted <jats:italic>MPC1<\/jats:italic> C2C12 cells verified the mechanism of variants: unstable MPC complex or ablated pyruvate uptake activity. Furthermore, we showed that glutamine and beta\u2010hydroxybutyrate were alternative substrates to maintain mitochondrial respiration when cells lack pyruvate. In conclusion, we expand the clinical phenotypes and genotypes associated with MPC deficiency, with our studies revealing glutamine as a potential therapy for MPC deficiency.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jimd.12462","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T06:25:36Z","timestamp":1638858336000},"page":"264-277","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Identification and characterization of novel <scp><i>MPC1<\/i><\/scp> gene variants causing mitochondrial pyruvate carrier deficiency"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6632-1793","authenticated-orcid":false,"given":"Huafang","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital Capital Medical University, National Center for Children's Health  Beijing 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