Cox7a1 mediated CIV dimerization impacts skeletal muscle physiology and cardiac injury response
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ABSTRACT:
PROVIDER: PRJNA1070616 | ENA |
REPOSITORIES: ENA
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Project description:The oxidative phosphorylation (OXPHOS) system is dynamic and the respiratory complexes (RCs) coexist with super-assembled quaternary structures called supercomplexes (SCs). How assembly occurs and the physiological role of supercomplex assembly is still under intensive investigation. The Cox7a family member Cox7a2l, also known as Scaf1, promotes CIII-CIV super assembly and energetic efficiency in zebrafish, mice, and humans. Here we studied the role of a second member of the Cox7a family, Cox7a1 in SC assembly and striated muscle physiology. We found that this protein drives CIV homodimer formation, which increases CIV activity. The substantial reduction in CIV2 formation led to a profound metabolic rearrangement with a consequent non-pathological loss of skeletal muscle performance. Ablation of Cox7a1 also rewired heart metabolism. Already in homeostatic conditions, cox7a1-/- hearts revealed a pro-regenerative metabolic profile. While overall cardiac function was not affected, the absence of Cox7a1 altered the cardiac regenerative response. The effects of cox7a1 and cox7a2l loss of function on skeletal muscle and myocardium physiology and injury response were not identical, revealing that there is a high specificity of Cox7a isoform in controlling OXPHOS assembly and striated muscle metabolism. While in both cases overall OXPHOS activity is modified, the loss of CIII-CIV heterodimer formation or CIV homodimer formation have very distinct metabolic and physiological consequences, highlighting the complexity of OXPHOS function and the importance of cox7a1 in striated muscle maturation.
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Project description:A mutation in the dimerization domain of the mouse glucocorticoid receptor (GR), dim1, has recently been shown to bind DNA and regulate gene expression. To expand these studies we created a stable osteosarcoma (U-2 OS) cell line expressing four mutations in the dimerization domain of the human GR, dim4 (N454D, A458T, R460D, D462C), and used whole human genome microarray analysis to compare differences in gene regulation between vehicle treated (CON) and those treated with the glucocorticoid receptor agonist dexamethasone (DEX) at 100nM concentration for 6 hours. Gene expression in U-2 OS hGRdim4 cells was measured after a 6 hour treatment with 100nM dexamethasone or vehicle (control) and the dexamethsone (dex) treated cells were compared to vehicle treated cells. The experiment was performed in triplicate.
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