Chemicals or mutations that target mitochondrial translation can rescue the respiratory deficiency of yeast bcs1 mutants

Bcs1p is a chaperone that is required for the incorporation of the Rieske subunit within complex III of the mitochondrial respiratory chain. Mutations in the human gene BCS1L (BCS1-like) are the most frequent nuclear mutations resulting in complex III-related pathologies. In yeast, the mimicking of...

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Veröffentlicht in:Biochimica et biophysica acta 2017-12, Vol.1864 (12), p.2297-2307
Hauptverfasser: Panozzo, C., Laleve, A., Tribouillard-Tanvier, D., Ostojić, J., Sellem, C.H., Friocourt, G., Bourand-Plantefol, A., Burg, A., Delahodde, A., Blondel, M., Dujardin, G.
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Sprache:eng
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Zusammenfassung:Bcs1p is a chaperone that is required for the incorporation of the Rieske subunit within complex III of the mitochondrial respiratory chain. Mutations in the human gene BCS1L (BCS1-like) are the most frequent nuclear mutations resulting in complex III-related pathologies. In yeast, the mimicking of some pathogenic mutations causes a respiratory deficiency. We have screened chemical libraries and found that two antibiotics, pentamidine and clarithromycin, can compensate two bcs1 point mutations in yeast, one of which is the equivalent of a mutation found in a human patient. As both antibiotics target the large mtrRNA of the mitoribosome, we focused our analysis on mitochondrial translation. We found that the absence of non-essential translation factors Rrf1 or Mif3, which act at the recycling/initiation steps, also compensates for the respiratory deficiency of yeast bcs1 mutations. At compensating concentrations, both antibiotics, as well as the absence of Rrf1, cause an imbalanced synthesis of respiratory subunits which impairs the assembly of the respiratory complexes and especially that of complex IV. Finally, we show that pentamidine also decreases the assembly of complex I in nematode mitochondria. It is well known that complexes III and IV exist within the mitochondrial inner membrane as supramolecular complexes III2/IV in yeast or I/III2/IV in higher eukaryotes. Therefore, we propose that the changes in mitochondrial translation caused by the drugs or by the absence of translation factors, can compensate for bcs1 mutations by modifying the equilibrium between illegitimate, and thus inactive, and active supercomplexes. [Display omitted] •Two antibiotics targeting the large mtrRNA compensate for yeast bcs1 mutants.•Absence of the translation factors Rrf1, or Mif3 also compensates for bcs1 mutants.•Antibiotics or the absence of Rrf1 cause an imbalanced synthesis of OXPHOS subunits.•Compensation of yeast bcs1 mutants is associated with a clear decrease in complex IV.•Pentamidine impairs the formation of complex I in nematodes.
ISSN:0167-4889
0006-3002
1879-2596
DOI:10.1016/j.bbamcr.2017.09.003