title: Ndufaf5 deficiency in the Dictyostelium model: new roles in autophagy and development.
abstract: Ndufaf5 (also known as C20orf7) is a mitochondrial complex I (CI) assembly factor whose mutations lead to human mitochondrial disease. Little is known about the function of the protein and the cytopathological consequences of the mutations. Disruption of Dictyostelium Ndufaf5 leads to CI deficiency and defects in growth and development. The predicted sequence of Ndufaf5 contains a putative methyltransferase domain. Site-directed mutagenesis indicates that the methyltransferase motif is essential for its function. Pathological mutations were recreated in the Dictyostelium protein and expressed in the mutant background. These proteins were unable to complement the phenotypes, which further validates Dictyostelium as a model of the disease. Chronic activation of AMP-activated protein kinase (AMPK) has been proposed to play a role in Dictyostelium and human cytopathology in mitochondrial diseases. However, inhibition of the expression of AMPK gene in the Ndufaf5-null mutant does not rescue the phenotypes associated with the lack of Ndufaf5, suggesting that novel AMPK-independent pathways are responsible for Ndufaf5 cytopathology. Of interest, the Ndufaf5-deficient strain shows an increase in autophagy. This phenomenon was also observed in a Dictyostelium mutant lacking MidA (C2orf56/PRO1853/Ndufaf7), another CI assembly factor, suggesting that autophagy activation might be a common feature in mitochondrial CI dysfunction.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Carilla-Latorre
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Annesley
authors.forename: Sandra
authors.initials: S
authors.lastname: Muñoz-Braceras
authors.forename: Paul R
authors.initials: PR
authors.lastname: Fisher
authors.forename: Ricardo
authors.initials: R
authors.lastname: Escalante
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D001343:Autophagy; D001665:Binding Sites; D004023:Dictyostelium / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000172:deficiency* / Q000235:genetics; D028361:Mitochondrial Diseases / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics; D016254:Mutagenesis, Insertional; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D015800:Protozoan Proteins; D008780:Methyltransferases; C532992:NDUFAF5 protein, human; D000263:Adenylate Kinase
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