Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy–like disease

Abstract

PurposeMembers of the mitochondrial carrier family (SLC25) transport metabolites, nucleotides, co-factors and inorganic ions across the mitochondrial inner membrane.MethodsWe identified a pathogenic variant in a novel mitochondrial carrier gene in a patient by whole exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modelling followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.ResultsThe patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid and quinolinic acid, which was confirmed in the patient’s urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis.ConclusionMitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease.

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

“…It has been suggested by the same authors that the ODC-catalyzed mitochondrial import of these two metabolites occurs via an exchange for matrix 2-oxoglutarate [142]. Although the disease-causing p.Lys232Arg substitution is a conservative mutation, it affects an SMS residue (Figure 1) of the matrix salt bridge network ( Figure 2B,D, at position 234), and renders SLC25A21 inactive [139]. In the SLC25A2-deficient patient, the urinary excretion of pipecolic and quinolinic acid, which are intermediates or by-products of the lysine and tryptophan degradation pathways, was observed together with that of 2-oxoadipate ( Figure 3).…”

“…A homozygous missense mutation in SLC25A21, giving rise to the p.Lys232Arg replacement in the oxodicarboxylate carrier ODC, segregated with a patient with spinal muscular atrophy-like disease and mitochondrial myopathy associated with reduced mitochondrial DNA copy number ( Table 1 and Table S1) [139]. ODC mainly transports 2-oxoadipate and 2-aminoadipate, that are produced from lysine and tryptophan degradation in the cytosol and are transported into the mitochondrial matrix, where they are oxidized and fed into the TCA cycle (Figure 3) [140,141].…”

Integrative omics approaches provide biological and clinical insights: examples from mitochondrial diseases

“…This indicates the importance of resolution and context in measuring metabolites; as resolution and context-specificity improve, GEMs become increasingly comprehensive and accurate. However, already in their current state, GEMs have been useful in exploring and gaining new insights into metabolomics (94). Considering modeling of large-scale metabolic data and its complexity, machine learning methods have proved useful in different steps of metabolism model building, including parameter determination and model optimization.…”

Mitochondrial diseases: expanding the diagnosis in the era of genetic testing

“…The protein transporter of 2-oxoadipate and 2-oxoglutarate across the IMM is SCL25A21. Biallelic variants in SCL25A21 inhibit the degradation of tryptophan and lysine, which in turn alters the generation of NADH and acetyl-CoA, with corresponding elevations in intracellular quinolinic acid and oxopate, and together they induce a neuropathy with a spinal muscular atrophy-like disease [314] . In addition to SCL25A12, glutamate and associated proton (H + ) is transported into the intermembrane space and into the matrix by SLC25A22 (GC1) and SLC25A18 (GC1).…”