To supply their energy needs, cells typically choose between utilizing glucose in the cytoplasm (aerobic glycolysis and lactic acid fermentation) or “burning” pyruvate in the mitochondria (mitochondrial carbohydrate oxidation). Although this is arguably the most fundamental metabolic decision that cells make, before 2012 it was not clear how cells import pyruvate into mitochondria to fuel ATP production. That year, Rutter, Thummel, and colleagues identified the heterodimeric MPC1/MPC2 complex as the mitochondrial pyruvate carrier.
The group identified and explained the severe metabolic defects found in families with mpc1 gene mutations. Rutter and collaborators have subsequently shown that the choice of whether to import pyruvate has far-reaching medical implications because stem cells and most cancer cells are glycolytic (the “Warburg Effect”). They showed that this is often because cells down-regulate MPC expression, and MPC re-expression reverses the Warburg Effect, impedes tumor growth, and drives cell differentiation. These discoveries have revolutionized our understanding of the role of metabolic decisions in determining cell state and fate.
A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, Cox JE, Cardon CM, Van Vranken JG, Dephoure N, Redin C, Boudina S, Gygi SP, Brivet M, Thummel CS, Rutter J. Science. 2012 Jul;337(6090):96.
A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Schell JC, Olson KA, Jiang L, Hawkins AJ, Van Vranken JG, Xie J, Egnatchik RA, Earl EG, DeBerardinis RJ, Rutter J. Molecular Cell. 2014 Nov;56(3):400.
A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC). Sandoval IT, Delacruz RG, Miller BN, Hill S, Olson KA, Gabriel AE, Boyd K, Satterfield C, Van Remmen H, Rutter J, Jones DA. Elife. 2017 Apr;6. pii: e22706.
Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Schell JC, Wisidagama DR, Bensard C, Zhao H, Wei P, Tanner J, Flores A, Mohlman J, Sorensen LK, Earl CS, Olson KA, Miao R, Waller TC, Delker D, Kanth P, Jiang L, DeBerardinis RJ, Bronner MP, Li DY, Cox JE, Christofk HR, Lowry WE, Thummel CS, Rutter J. Nature Cell Biology. 2017 Sep;19(9):1027.
Regulation of tumor initiation by the mitochondrial pyruvate carrier. Bensard CL, Wisidigama DR, Olson KA, Berg JA, Krah NM, Schell JC, Bott AJ, Nowinski SM, Wei P, Dove KK, Tanner JM, Panic V, Fogarty SA, Cluntun A, Lettlova S, Earl CS, Namnath DF, Vázquez-Arregun K, Villanueva CJ, Tantin D, Murtaugh LC, Evason KJ, Ducker GS, Thummel CS, Rutter J. Cell Metabolism. 2019. Dec;Epublication ahead of print.
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University of Utah Health: Rewiring Metabolism Slows Cancer Growth