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

TL;DR

A mouse model of MEPAN reveals how mitochondrial fatty acid synthesis affects iron-sulfur clusters and energy production in the brain.

Contribution

The study identifies a novel role for MECR in ACP acylation and its impact on mitochondrial supercomplexes and iron-sulfur cluster biogenesis.

Findings

MECR mutations disrupt iron-sulfur cluster biogenesis and OXPHOS supercomplex formation.

Loss of MECR leads to reduced protein lipoylation and mitochondrial dysfunction in the brain.

ACP acylation is critical for LYRM protein interactions and mitochondrial complex assembly.

Abstract

The mitochondrial fatty acid synthesis pathway is necessary for mitochondrial ATP production, but its mechanism is unknown. Individuals with mutations in MECR, encoding the last step in mtFASII, have early-onset neurological dysfunction. We describe characterization of a mouse model of MEPAN and the mechanism by which mtFASII causes neurological dysfunction. Dysfunctional MECR results in loss of iron–sulfur center cluster biogenesis complexes and altered formation of complexes and supercomplexes of OXPHOS through the loss of acylation of ACP and its interactions with LYRM proteins. These results offer therapeutic targets for treatment of MEPAN and mitochondrial modulation in general.

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 unique pathways for therapeutics.

Figures