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Jiang, H.* ; Alahmad, A.* ; Fu, S.* ; Fu, X.* ; Liu, Z.* ; Han, X.* ; Li, L.* ; Song, T.* ; Xu, M.* ; Liu, S.* ; Wang, J.* ; Albash, B.* ; Alaqeel, A.* ; Catalina, V. ; Prokisch, H. ; Taylor, R.W.* ; McFarland, R.* ; Fang, F.*

Identification and characterisation of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency.

J. Inherit. Metab. Dis., DOI: 10.1002/jimd.12462 (2022)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Pyruvate, the end product of glycolysis, is a key metabolic molecule enabling mitochondrial adenosine triphosphate synthesis and takes part in multiple biosynthetic pathways within mitochondria. The mitochondrial pyruvate carrier (MPC) plays a vital role in transporting pyruvate from the cytosol into the organelle. In humans, MPC is a hetero-oligomeric complex formed by the MPC1 and MPC2 paralogs that are both necessary to stabilize each other and form a functional MPC. MPC deficiency (OMIM#614741) due to pathogenic MPC1 variants is a rare autosomal recessive disease involving developmental delay, microcephaly, growth failure, and increased serum lactate and pyruvate. To date, two MPC1 variants in four cases have been reported, though only one with a detailed clinical description. Herein, we report three novel pathogenic MPC1 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-like syndrome. Functional analysis in primary fibroblasts from the patients revealed decreased expression of MPC1 and MPC2. We rescued pyruvate-driven oxygen consumption rate in patient's fibroblasts by reconstituting with wild-type MPC1. Complementing homozygous MPC1 mutant cDNA with CRISPR-deleted MPC1 C2C12 cells verified the mechanism of variants: unstable MPC complex or ablated pyruvate uptake activity. Furthermore, we showed that glutamine and beta-hydroxybutyrate 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Leigh-like Syndrome ; Mpc1 ; Glutamine ; Mitochondria ; Mitochondrial Pyruvate Carrier Deficiency ; Treatment; Disease; Glutamine; Patient
ISSN (print) / ISBN 0141-8955
e-ISSN 1573-2665
Journal Journal of Inherited Metabolic Disease
Publisher Springer
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Grants PerMiM project
Wellcome Trust Centre for Mitochondrial Research
Mitochondrial Disease Patient Cohort
Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease
China Association Against Epilepsy Scientific Research Project
Capital Health Research and Development of Special
Beijing Foreign High-level Talents Foundation Project
Beijing Children's Hospital for Children Medication Foundation