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

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

  • Genet Med. 2018 Oct;20(10):1224-1235. doi: 10.1038/gim.2017.251.
Veronika Boczonadi 1,  Martin S King 2,  Anthony C Smith 2,  Monika Olahova 3,  Boglarka Bansagi 1,  Andreas Roos 1 4,  Filmon Eyassu 2,  Christoph Borchers 5,  Venkateswaran Ramesh 6,  Hanns Lochmüller 1,  Tuomo Polvikoski 7,  Roger G Whittaker 8,  Angela Pyle 1,  Helen Griffin 1,  Robert W Taylor 3,  Patrick F Chinnery 2 9,  Alan J Robinson 2,  Edmund R S Kunji 10,  Rita Horvath 11
Affiliations

Affiliations

  • 1 Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
  • 2 Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 3 Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
  • 4 Leibniz Institute of Analytic Sciences (ISAS), Dortmund, Germany.
  • 5 UVic-Genome BC Proteomics Centre, Vancouver, British Columbia, Canada.
  • 6 Department of Paediatric Neurology, Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, UK.
  • 7 Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
  • 8 Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
  • 9 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
  • 10 Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. [email protected].
  • 11 Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. [email protected].
PMID: 29517768 DOI: 10.1038/gim.2017.251
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.

Keywords

metabolite transport; metabolomics; mitochondrial respiratory chain deficiency; neural toxicity; spinal motor atrophy.

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