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Fine-tuning of the respiratory complexes stability and supercomplexes assembly in cells defective of complex III
- Source :
- Biochim Biophys Acta Bioenerg
- Publication Year :
- 2019
-
Abstract
- The respiratory complexes are organized in supramolecular assemblies called supercomplexes thought to optimize cellular metabolism under physiological and pathological conditions. In this study, we used genetically and biochemically well characterized cells bearing the pathogenic microdeletion m.15,649–15,666 (ΔI300-P305) in MT-CYB gene, to investigate the effects of an assembly-hampered CIII on the re-organization of supercomplexes. First, we found that this mutation also affects the stability of both CI and CIV, and evidences the occurrence of a preferential structural interaction between CI and CIII(2), yielding a small amount of active CI+CIII(2) super-complex. Indeed, a residual CI+CIII combined redox activity, and a low but detectable ATP synthesis driven by CI substrates are detectable, suggesting that the assembly of CIII into the CI+CIII(2) supercomplex mitigates the detrimental effects of MT-CYB deletion. Second, measurements of oxygen consumption and ATP synthesis driven by NADH-linked and FADH(2)-linked substrates alone, or in combination, indicate a common ubiquinone pool for the two respiratory pathways. Finally, we report that prolonged incubation with rotenone enhances the amount of CI and CIII(2), but reduces CIV assembly. Conversely, the antioxidant N-acetylcysteine increases CIII(2) and CIV(2) and partially restores respirasome formation. Accordingly, after NAC treatment, the rate of ATP synthesis increases by two-fold compared with untreated cell, while the succinate level, which is enhanced by the homoplasmic mutation, markedly decreases. Overall, our findings show that fine-tuning the supercomplexes stability improves the energetic efficiency of cells with the MT-CYB microdeletion.
- Subjects :
- 0301 basic medicine
N-acetylcysteine, rotenone
Biophysics
MT-CYB gene in-frame microdeletion
Mitochondrion
medicine.disease_cause
Biochemistry
Article
Electron Transport Complex IV
03 medical and health sciences
chemistry.chemical_compound
Electron Transport Complex III
0302 clinical medicine
Adenosine Triphosphate
Oxygen Consumption
Rotenone
medicine
Animals
Mutation
Electron Transport Complex I
ATP synthase
biology
Animal
Cell Biology
Mitochondria
Respiratory chain supercomplexe
030104 developmental biology
chemistry
Cytochrome b depletion complex III dysfunction
Coenzyme Q – cytochrome c reductase
Respirasome
Mitochondrial Membranes
biology.protein
Mitochondrial Membrane
lipids (amino acids, peptides, and proteins)
Adenosine triphosphate
Oxidation-Reduction
030217 neurology & neurosurgery
Gene Deletion
Subjects
Details
- ISSN :
- 18792650
- Volume :
- 1861
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Biochimica et biophysica acta. Bioenergetics
- Accession number :
- edsair.doi.dedup.....6a188689001c1f1bfd2404aac9948a74