2022
DOI: 10.1093/brain/awac444
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MPC2variants disrupt mitochondrial pyruvate metabolism and cause an early-onset mitochondriopathy

Abstract: Pyruvate is an essential metabolite produced by glycolysis in the cytosol and must be transported across the inner mitochondrial membrane (IMM) into the mitochondrial matrix, where it is oxidized to fuel mitochondrial respiration. Pyruvate import is performed by Mitochondrial Pyruvate Carrier (MPC), a hetero-oligomeric complex composed by interdependent subunits MPC1 and MPC2. Pathogenic variants in MPC1 gene disrupt mitochondrial pyruvate uptake and oxidation and cause autosomal-recessive early-onset neurolog… Show more

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Cited by 6 publications
(5 citation statements)
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“…3,6,10 Germline deletion of the Mpc gene was found to cause early embryo death in mice, [11][12][13] and mutations in the MPC1 and MPC2 in the population were also found to cause significant growth retardation and death in utero or childhood. 14,15 Lactic acidosis, hypotonia, malformation, and encephalopathy are the most common symptoms of MPC mutations with loss of function, and these patients are often in critical condition. 14,15 Conditional loss of MPC in the heart 10 and central nervous system (CNS) 16 of mice leads to progressive cardiomyopathy and sensitivity to epileptic seizures, respectively.…”
Section: Mpc and Its Involvement In Diseases Mpc Mechanismmentioning
confidence: 99%
See 1 more Smart Citation
“…3,6,10 Germline deletion of the Mpc gene was found to cause early embryo death in mice, [11][12][13] and mutations in the MPC1 and MPC2 in the population were also found to cause significant growth retardation and death in utero or childhood. 14,15 Lactic acidosis, hypotonia, malformation, and encephalopathy are the most common symptoms of MPC mutations with loss of function, and these patients are often in critical condition. 14,15 Conditional loss of MPC in the heart 10 and central nervous system (CNS) 16 of mice leads to progressive cardiomyopathy and sensitivity to epileptic seizures, respectively.…”
Section: Mpc and Its Involvement In Diseases Mpc Mechanismmentioning
confidence: 99%
“…14,15 Lactic acidosis, hypotonia, malformation, and encephalopathy are the most common symptoms of MPC mutations with loss of function, and these patients are often in critical condition. 14,15 Conditional loss of MPC in the heart 10 and central nervous system (CNS) 16 of mice leads to progressive cardiomyopathy and sensitivity to epileptic seizures, respectively.…”
Section: Mpc and Its Involvement In Diseases Mpc Mechanismmentioning
confidence: 99%
“…Reports of humans with MPC mutations show very severe phenotypes, supporting the functional importance of this protein [5], [6], [7], [8] . Global knockout of MPC in mice is lethal in the embryonic stages [9], [10], [11], [12] , but liver-specific Mpc deletion in mice has shown beneficial metabolic effects [13], [14], [15], [16] , leading to an interest in developing an MPC inhibitor as a possible therapeutic [3] .…”
Section: Introductionmentioning
confidence: 98%
“…Germline deletion of either Mpc gene results in early embryonic lethality in mice [16][17][18][19]. In people, rare mutations in MPC1 and MPC2 have been identified, and these also frequently result in significant growth and developmental delay and lethality in utero or in childhood [20][21][22]. The primary phenotypes of loss-of-function MPC mutations consist of lactic acidosis, hypotonia, dysmorphia, and encephalopathy, and patients with these variants are usually severely ill [20][21][22].…”
Section: Introductionmentioning
confidence: 99%
“…In people, rare mutations in MPC1 and MPC2 have been identified, and these also frequently result in significant growth and developmental delay and lethality in utero or in childhood [20][21][22]. The primary phenotypes of loss-of-function MPC mutations consist of lactic acidosis, hypotonia, dysmorphia, and encephalopathy, and patients with these variants are usually severely ill [20][21][22]. Conditional loss of the MPC in the heart [15,23,24] and the central nervous system [25] in mice leads to progressive cardiomyopathy and sensitivity to seizures, respectively.…”
Section: Introductionmentioning
confidence: 99%