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.