MassIVE MSV000099206

Complete Public PXD068434

A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron sulfur cluster and supercomplex formation

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Description

MEPAN (Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration) is an early onset movement disorder characterized by ataxia, dysarthria, and optic atrophy. Here we report the creation of a mouse model of MEPAN with patient-similar compound heterozygous mutations in the Mecr gene. The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain. MECR catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII), and the mechanism by which loss of mtFASII leads to neurological disease is unknown. LC-MS/MS based proteomic analysis of Mecr mutant cerebella identified loss of subunits of complex I of oxidative phosphorylation (OXPHOS) and subunits of the iron sulfur cluster assembly (ISC) complex. Native gels revealed altered OXPHOS complex and supercomplex formation, and changes in binding of the acyl carrier protein (ACP) to mitochondrial complexes. These results demonstrate that MECR plays a key role in the acylation of ACP which is necessary for ACP-LYRM mediated supercomplex modulation and ISC biogenesis and suggest new pathways for therapeutics. [doi:10.25345/C5P55DW1F] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: mitochondria ; cerebellum ; mepan ; mecr ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Douglas C Wallace, Children's Hospital of Philadelphia, United States
Submitting User: janssenk
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