Tissue-specific adaptations to cytochrome c oxidase deficiency shape physiological outcomes
It becomes increasingly clear that the tissue specificity of mitochondrial diseases might in part rely on their ability to compensate for mitochondrial defects, contributing to the heterogeneous nature of mitochondrial diseases. Here, we investigated tissue-specific responses to cytochrome c oxidase...
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Veröffentlicht in: | Biochimica et biophysica acta. Molecular basis of disease 2024-11, Vol.1871 (3), p.167567 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | It becomes increasingly clear that the tissue specificity of mitochondrial diseases might in part rely on their ability to compensate for mitochondrial defects, contributing to the heterogeneous nature of mitochondrial diseases. Here, we investigated tissue-specific responses to cytochrome c oxidase (CIV or COX) deficiency using a mouse model with heart and skeletal muscle-specific depletion of the COX assembly factor COX10. At three weeks of age, both tissues exhibit pronounced CIV depletion but respond differently to oxidative phosphorylation (OXPHOS) impairment. Heart-specific COX10 depletion caused severe dilated cardiomyopathy, while skeletal muscle experiences less damage. Cardiac CIV deficiency triggered extensive metabolic remodelling and stress response activation, potentially worsening cardiomyopathy, whereas skeletal muscle showed no stress response or significant metabolic changes. Our findings highlight distinct tissue capacities for managing CIV deficiency, explaining how identical primary defects can lead to different phenotypic outcomes and contribute to the heterogeneous progression of mitochondrial diseases.
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•Complex IV deficiency can be coped in a tissue-specific manner leading to different phenotypic outcomes.•Exclusively cardiac loss of complex IV is accompanied by extensive metabolic remodelling and stress response.•C-myc plays a key role in accomplishing to a response to complex IV dysfunction in heart. |
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ISSN: | 0925-4439 1879-260X 1879-260X |
DOI: | 10.1016/j.bbadis.2024.167567 |