Identification and characterization of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency.
Leigh-like syndrome
MPC1
glutamine
mitochondria
mitochondrial pyruvate carrier deficiency
treatment
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
revised:
30
11
2021
received:
05
10
2021
accepted:
03
12
2021
pubmed:
8
12
2021
medline:
10
5
2022
entrez:
7
12
2021
Statut:
ppublish
Résumé
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.
Substances chimiques
MPC1 protein, human
0
Mitochondrial Membrane Transport Proteins
0
Monocarboxylic Acid Transporters
0
Glutamine
0RH81L854J
Pyruvic Acid
8558G7RUTR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
264-277Subventions
Organisme : Medical Research Council
ID : MR/S005021/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203105/Z/16/Z
Pays : United Kingdom
Informations de copyright
© 2021 SSIEM.
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