Identification and characterization of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency

Abstract

Pyruvate, the end product of glycolysis, is a key metabolic molecule enabling mitochondrial adenosine triphosphate synthesis and takes part in multiple biosynthetic pathways within mitochondria. The mitochondrial pyruvate carrier (MPC) plays a vital role in transporting pyruvate from the cytosol into the organelle. In humans, MPC is a hetero-oligomeric complex formed by the MPC1 and MPC2 paralogs that are both necessary to stabilize each other and form a functional MPC. MPC deficiency (OMIM#614741) due to pathogenic MPC1 variants is a rare autosomal recessive disease involving developmental delay, microcephaly, growth failure, and increased serum lactate and pyruvate. To date, two MPC1 variants in four cases have been reported, though only one with a detailed clinical description. Herein, we report three novel pathogenic MPC1 variants in six patients from three unrelated families, identified within European, Kuwaiti, and Chinese mitochondrial disease patient cohorts, one of whom presented as a Leigh-like syndrome. Functional analysis in primary fibroblasts from the patients revealed decreased expression of MPC1 and MPC2. We rescued pyruvate-driven oxygen consumption rate in patient's fibroblasts by reconstituting with wild-type MPC1. Complementing homozygous MPC1 mutant cDNA with CRISPR-deleted MPC1 C2C12 cells verified the

MPC2variants disrupt mitochondrial pyruvate metabolism and cause an early-onset mitochondriopathy

“…Once imported into mitochondria by the MPC, its metabolism is tuned by mainly two enzymes: pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-coA, and pyruvate carboxylase (PC), which catalyses the conversion of pyruvate to oxaloacetate in fasting conditions. Numerous cases of pathogenic variants disrupting the activity of PDH or PC, and recently MPC1, have been described, 14 , 17 , 18 all leading to severe diseases characterized by various phenotypes including lactic acidosis, hypotonia, developmental delay, seizures and even premature death. Here, we describe the first pathogenic MPC2 variants associated with an equally devastating multisystemic dysfunction in children.…”

“…In rodents, MPC dysfunction contributes to cell proliferation in colorectal or prostate cancer 8,9 as well as pathological cardiac hypertrophy 10,11 , diabetic nephropathy 12 and it has also been shown that MPC is required for myocardial stress adaptation 13 . In humans, loss-of-function MPC1 variants prevented MPC assembly and mitochondrial pyruvate uptake 5,15 . To date, there are only 10 patients reported in the literature 15 , with clinical presentations including hypotonia, encephalopathy and frequent early death 14,15 .…”

“…In humans, loss-of-function MPC1 variants prevented MPC assembly and mitochondrial pyruvate uptake 5,15 . To date, there are only 10 patients reported in the literature 15 , with clinical presentations including hypotonia, encephalopathy and frequent early death 14,15 .…”

“… 13 In humans, loss-of-function MPC1 variants prevented MPC assembly and mitochondrial pyruvate uptake. 5 , 14 To date, there are only 10 patients reported in the literature, 14 with clinical presentations including hypotonia, encephalopathy and frequent early death. 14 , 15 Typically, high lactate and pyruvate concentrations with a normal L/P ratio are found in fluids of patients, usually suggesting PDH deficiency.…”

“… 5 , 14 To date, there are only 10 patients reported in the literature, 14 with clinical presentations including hypotonia, encephalopathy and frequent early death. 14 , 15 Typically, high lactate and pyruvate concentrations with a normal L/P ratio are found in fluids of patients, usually suggesting PDH deficiency. However, MPC impairment should be considered for similar cases.…”