ArticleJCI insight2019
Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 33 citations in OpenAlex.
- TruncatingbioRxiv : the preprint server for biology · 2026Article
- MPC-mediated lactate production drives histone lactylation in dendritic cells to affect tumor progression and immunotherapy.Cellular and molecular life sciences : CMLS · 2025Article
- The Role of Mitochondrial Pyruvate Carrier in Neurological Disorders.Molecular neurobiology · 2025Review
- UK5099 Inhibits the NLRP3 Inflammasome Independently of its Long-Established Target Mitochondrial Pyruvate Carrier.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Computational structural prediction and chemical inhibition of the human mitochondrial pyruvate carrier protein heterodimer complex.bioRxiv : the preprint server for biology · 2024Article
- Glucose-derived glutamate drives neuronal terminal differentiation in vitro.EMBO reports · 2024Article
- Mitochondrial pyruvate carrier 2 mitigates acute kidney injury via sustaining mitochondrial metabolism.International journal of biological sciences · 2024Article
- Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition.Acta physiologica (Oxford, England) · 2023Review
- The mitochondrial pyruvate carrier complex potentiates the efficacy of proteasome inhibitors in multiple myeloma.Blood advances · 2023Article
- MPC2 variants disrupt mitochondrial pyruvate metabolism and cause an early-onset mitochondriopathy.Brain : a journal of neurology · 2023Article
- Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier.Nutrients · 2022Article
- The mitochondrial pyruvate carrier at the crossroads of intermediary metabolism.American journal of physiology. Endocrinology and metabolism · 2022Review
- Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.eLife · 2022Article
- Structural Insights into the Human Mitochondrial Pyruvate Carrier Complexes.Journal of chemical information and modeling · 2021Article
- Learning from Yeast about Mitochondrial Carriers.Microorganisms · 2021Review
- Dual-process brain mitochondria isolation preserves function and clarifies protein composition.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling.Frontiers in molecular neuroscience · 2021Article
- Metabolite regulation of the mitochondrial calcium uniporter channel.Cell calcium · 2020Article
- Sequence Features of Mitochondrial Transporter Protein Families.Biomolecules · 2020Review
- Insights on the Quest for the Structure-Function Relationship of the Mitochondrial Pyruvate Carrier.Biology · 2020Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 3 countries.
Funding
Abstract
The Mitochondrial Pyruvate Carrier (MPC) occupies a central metabolic node by transporting cytosolic pyruvate into the mitochondrial matrix and linking glycolysis with mitochondrial metabolism. Two reported human MPC1 mutations cause developmental abnormalities, neurological problems, metabolic deficits, and for one patient, early death. We aimed to understand biochemical mechanisms by which the human patient C289T and T236A MPC1 alleles disrupt MPC function. MPC1 C289T encodes two protein variants, a mis-spliced, truncation mutant (A58G) and a full length point mutant (R97W). MPC1 T236A encodes a full length point mutant (L79H). Using human patient fibroblasts and complementation of CRISPR-deleted, MPC1 null mouse C2C12 cells, we investigated how MPC1 mutations cause MPC deficiency. Truncated MPC1 A58G protein was intrinsically unstable and failed to form MPC complexes. The MPC1 R97W protein was less stable but when overexpressed formed complexes with MPC2 that retained pyruvate transport activity. Conversely, MPC1 L79H protein formed stable complexes with MPC2, but these complexes failed to transport pyruvate. These findings inform MPC structure-function relationships and delineate three distinct biochemical pathologies resulting from two human patient MPC1 mutations. They also illustrate an efficient gene pass-through system for mechanistically investigating human inborn errors in pyruvate metabolism.
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Registered trials
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