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

TitleMitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.
Publication TypeJournal Article
Year of Publication2018
AuthorsBoczonadi, V, King, MS, Smith, AC, Oláhová, M, Bansagi, B, Roos, A, Eyassu, F, Borchers, C, Ramesh, V, Lochmüller, H, Polvikoski, T, Whittaker, RG, Pyle, A, Griffin, H, Taylor, RW, Chinnery, PF, Robinson, AJ, Kunji, ERS, Horvath, R
JournalGenet Med
Volume20
Issue10
Pagination1224-1235
Date Published2018 10
ISSN1530-0366
KeywordsAdipates, Apoptosis, Cell Line, Dicarboxylic Acid Transporters, DNA, Mitochondrial, Fibroblasts, Homozygote, Humans, Mitochondria, Motor Neurons, Muscular Atrophy, Spinal, Mutation, Pipecolic Acids, Quinolinic Acid
Abstract

PURPOSE: To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.

METHODS: We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.

RESULTS: The 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.

CONCLUSION: Mitochondrial 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.

DOI10.1038/gim.2017.251
Alternate JournalGenet. Med.
Citation Key10.1038/gim.2017.251
PubMed ID29517768
PubMed Central IDPMC6004311
Grant ListMC_U105674181 / / Medical Research Council / United Kingdom
G1000848 / / Medical Research Council / United Kingdom
MC_UP_1501/2 / / Medical Research Council / United Kingdom
201064/Z/16/Z / / Wellcome Trust / United Kingdom
309548 / / European Research Council / International
MR/N025431/1 / / Medical Research Council / United Kingdom
G0800674 / / Medical Research Council / United Kingdom
203105/Z/16/Z / / Wellcome Trust / United Kingdom
MC_U105663139 / / Medical Research Council / United Kingdom
109915/Z/15/Z / / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom
109915 / / Wellcome Trust / United Kingdom