MPC2 variants disrupt mitochondrial pyruvate metabolism and cause an early-onset mitochondriopathy

Abstract Pyruvate is an essential metabolite produced by the glycolytic pathway 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), which is a hetero-oligomeric complex composed by interdependent subunits MPC1 and MPC2. Pathogenic variants in MPC1 gene disrupt mitochondrial pyruvate uptake and oxidation and it was associated to autosomal-recessive early-onset neurological dysfunction in humans. However, no pathogenic variants have been related to the MPC2 gene. The present work describes the first pathogenic variants in MPC2 associated with human disease in four patients from two unrelated families. In the first family, patients presented with antenatal developmental abnormalities, harbored a homozygous c.148T>C (p.Trp50Arg) variant. In the second family, patients presented with infantile encephalopathy carried missense c.2T>G (p.Met1?) variant disrupting the initiation codon. Patient-derived skin fibroblasts exhibit decreased pyruvate-driven oxygen consumption rates with normal activities of the pyruvate dehydrogenase complex and mitochondrial respiratory chain and no defects in mitochondrial content nor morphology. Re-expression of wild type MPC2 restored pyruvate-dependent respiration rates in patient-derived fibroblasts. The discovery of pathogenic variants in MPC2 therefore broadens the clinical and genetic landscape associated with inborn errors in pyruvate metabolism.