Pyruvate is oxidized to acetyl‐CoA by pyruvate dehydrogenase which is localized in the mitochondrial matrix. The mitochondrial pyruvate carrier (MPC) is composed of SLC54 family members (MPC1 and MPC2) [1,4], which form functional hetero-dimers [7-8]. The MPC is expressed in the inner mitochondrial membrane and involved in the import of pyruvate into mitochondria [1,4]. Ubiquitous disruption of either MPC1 or MPC2 expression results in embryonic lethality [10-11]. Clinically relevant concentrations of the insulin sensitizers, thiazolidinediones, inhibit the MPC [2]. Other clinically relevant inhibitors of the MPC complex are lonidamine [6-7], quinolone antibacterials [5], entacapone and nitrofurantoin [7].

SLC54 family of transporters form hetero-dimers responsible for the accumulation of pyruvate into mitochondria, to link glycolysis with oxidative phosphorylation.

* Key recommended reading is highlighted with an asterisk

* Bader DA, Hartig SM, Putluri V, Foley C, Hamilton MP, Smith EA, Saha PK, Panigrahi A, Walker C, Zong L et al.. (2019) Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer. Nat Metab, 1 (1): 70-85. [PMID:31198906]

* Harrison SA, Alkhouri N, Davison BA, Sanyal A, Edwards C, Colca JR, Lee BH, Loomba R, Cusi K, Kolterman O et al.. (2020) Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study. J Hepatol, 72 (4): 613-626. [PMID:31697972]

Koh E, Kim YK, Shin D, Kim KS. (2018) MPC1 is essential for PGC-1α-induced mitochondrial respiration and biogenesis. Biochem J, 475 (10): 1687-1699. [PMID:29669911]

* McCommis KS, Hodges WT, Brunt EM, Nalbantoglu I, McDonald WG, Holley C, Fujiwara H, Schaffer JE, Colca JR, Finck BN. (2017) Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology, 65 (5): 1543-1556. [PMID:28027586]

Schell JC, Wisidagama DR, Bensard C, Zhao H, Wei P, Tanner J, Flores A, Mohlman J, Sorensen LK, Earl CS et al.. (2017) Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat Cell Biol, 19 (9): 1027-1036. [PMID:28812582]

Tang XP, Chen Q, Li Y, Wang Y, Zou HB, Fu WJ, Niu Q, Pan QG, Jiang P, Xu XS et al.. (2019) Mitochondrial pyruvate carrier 1 functions as a tumor suppressor and predicts the prognosis of human renal cell carcinoma. Lab Invest, 99 (2): 191-199. [PMID:30291323]

Taylor EB. (2017) Functional Properties of the Mitochondrial Carrier System. Trends Cell Biol, 27 (9): 633-644. [PMID:28522206]

* Tompkins SC, Sheldon RD, Rauckhorst AJ, Noterman MF, Solst SR, Buchanan JL, Mapuskar KA, Pewa AD, Gray LR, Oonthonpan L et al.. (2019) Disrupting Mitochondrial Pyruvate Uptake Directs Glutamine into the TCA Cycle away from Glutathione Synthesis and Impairs Hepatocellular Tumorigenesis. Cell Rep, 28 (10): 2608-2619.e6. [PMID:31484072]

* Yiew NKH, Finck BN. (2022) The mitochondrial pyruvate carrier at the crossroads of intermediary metabolism. Am J Physiol Endocrinol Metab, 323 (1): E33-E52. [PMID:35635330]

1. Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, Cox JE, Cardon CM, Van Vranken JG, Dephoure N et al.. (2012) A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science, 337 (6090): 96-100. [PMID:22628558]

2. Divakaruni AS, Wiley SE, Rogers GW, Andreyev AY, Petrosyan S, Loviscach M, Wall EA, Yadava N, Heuck AP, Ferrick DA et al.. (2013) Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier. Proc Natl Acad Sci U S A, 110 (14): 5422-7. [PMID:23513224]

3. Halestrap AP. (1975) The mitochondrial pyruvate carrier. Kinetics and specificity for substrates and inhibitors. Biochem J, 148 (1): 85-96. [PMID:1156402]

4. Herzig S, Raemy E, Montessuit S, Veuthey JL, Zamboni N, Westermann B, Kunji ER, Martinou JC. (2012) Identification and functional expression of the mitochondrial pyruvate carrier. Science, 337 (6090): 93-6. [PMID:22628554]

5. Hodges WT, Jarasvaraparn C, Ferguson D, Griffett K, Gill LE, Chen Y, Ilagan MXG, Hegazy L, Elgendy B, Cho K et al.. (2022) Mitochondrial pyruvate carrier inhibitors improve metabolic parameters in diet-induced obese mice. J Biol Chem, 298 (2): 101554. [PMID:34973337]

6. Nancolas B, Guo L, Zhou R, Nath K, Nelson DS, Leeper DB, Blair IA, Glickson JD, Halestrap AP. (2016) The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters. Biochem J, 473 (7): 929-36. [PMID:26831515]

7. Tavoulari S, Schirris TJJ, Mavridou V, Thangaratnarajah C, King MS, Jones DTD, Ding S, Fearnley IM, Kunji ERS. (2022) Key features of inhibitor binding to the human mitochondrial pyruvate carrier hetero-dimer. Mol Metab, 60: 101469. [PMID:35278701]

8. Tavoulari S, Thangaratnarajah C, Mavridou V, Harbour ME, Martinou JC, Kunji ER. (2019) The yeast mitochondrial pyruvate carrier is a hetero-dimer in its functional state. EMBO J, 38 (10). [PMID:30979775]

9. Vanderperre B, Cermakova K, Escoffier J, Kaba M, Bender T, Nef S, Martinou JC. (2016) MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells. J Biol Chem, 291 (32): 16448-61. [PMID:27317664]

10. Vanderperre B, Herzig S, Krznar P, Hörl M, Ammar Z, Montessuit S, Pierredon S, Zamboni N, Martinou JC. (2016) Embryonic Lethality of Mitochondrial Pyruvate Carrier 1 Deficient Mouse Can Be Rescued by a Ketogenic Diet. PLoS Genet, 12 (5): e1006056. [PMID:27176894]

11. Vigueira PA, McCommis KS, Schweitzer GG, Remedi MS, Chambers KT, Fu X, McDonald WG, Cole SL, Colca JR, Kletzien RF et al.. (2014) Mitochondrial pyruvate carrier 2 hypomorphism in mice leads to defects in glucose-stimulated insulin secretion. Cell Rep, 7 (6): 2042-2053. [PMID:24910426]

Subcommittee members: Sotiria Tavoulari Medical Research Council Mitochondrial Biology Unit University of Cambridge The Keith Peters Building Cambridge Biomedical Campus Hills Road Cambridge CB2 0XY UK Calum Wilson Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde 161 Cathedral Street Glasgow, G4 0RE