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Human mitochondrial translation : what makes the proteins and how are they escorted to their final destination ?

Vendredi 6 avril 2018 10:00-11:00 - Robert LIGHTOWLERS - Newcastle University, invité par N. Bonnefoy

Human mitochondrial translation : what makes the proteins and how are they escorted to their final destination ?

Résumé : The function of human mitochondrial insertase Oxa1L, the human homolog of yeast Oxa1 (first described by members of CGM in Gif-Sur-Yvette) has remained contentious since its identification over 20 years ago. Recently, we have identified a patient with a biallelic mutation in OXA1L that causes a mitochondrial disease due to a combined oxidative phosphorylation deficiency. Previous experiments with shRNA depletion of human Oxa1L reported a defect in complexes I and V but spared any involvement in cytochrome c oxidase assembly (COX ; complex IV), a surprising result as Oxa1L had been expected to be essential for the insertion of all mtDNA encoded components. Patient muscle and fibroblasts show a decrease in Oxa1L but also a depletion of complex IV and V with a relative sparing of complex I, a phenotype rescued by expression of wild type Oxa1L. Targeted depletion of OXA1L in Drosophila melanogaster caused defects in the assembly of complexes I, IV and V. Targeted disruption of Oxa1L in human HEK293T cells required the co-expression of exogenous Oxa1L to prevent lethality, but the controlled loss of Oxa1L resulted in a substantial loss of complexes I, III, IV and V. Neuropathological experiments from the Oxa1L-deficient patient, however, indicate an isolated complex I deficiency. Taken together, whilst our data verify the pathogenicity of mutations in Oxa1L and demonstrate it is required for the assembly of multiple OXPHOS complexes, we find striking tissue and cell specific variation, perhaps implying the existence of other tissue-specific insertases involved in mitochondrial protein synthesis.

Lieu : Bibliothèque, Bât. 34 - Campus de Gif-sur-Yvette

Pour en savoir plus sur cet événement, consultez l'article Département Biologie Cellulaire