Acetylation of NDUFA13 at K7 Senses OXPHOS Dysfunction to Disrupt Prohibitin Scaffolds and Drive Cristae Remodelling in Heart Failure

Nan, J.; Yang, X.; Lin, Y.; Shen, J.; Chen, H.; Xu, Z.; Ye, J.; Wang, Y.; Xiong, D.; Ke, C.; Zhu, L.; Kong, X.; Zhong, Z.; Ren, T.; Jiang, J.; Wang, X.; Wang, B.; Zhao, D.; Li, Z.-z.; Shao, Z.; Liu, B.; He, X.

doi:10.64898/2026.10.26.761921

bioRxiv · 10.64898/2026.10.26.761921

Acetylation of NDUFA13 at K7 Senses OXPHOS Dysfunction to Disrupt Prohibitin Scaffolds and Drive Cristae Remodelling in Heart Failure

Nan, J.·Yang, X.·Lin, Y.·Shen, J.·Chen, H.·Xu, Z.·Ye, J.·Wang, Y.·Xiong, D.·Ke, C.·Zhu, L.·Kong, X.·Zhong, Z.·Ren, T.·Jiang, J.·Wang, X.·Wang, B.·Zhao, D.·Li, Z.-z.·Shao, Z.·Liu, B.·He, X.

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Abstract

Mitochondrial cristae disintegration is a hallmark of heart failure, yet how oxidative phosphorylation (OXPHOS) dysfunction triggers this structural collapse remains unclear. Here we identify acetylation of the complex I subunit NDUFA13 at lysine 7 (K7) as a metabolic sensor coupling OXPHOS dysfunction to cristae remodelling. OXPHOS inhibition drove NDUFA13-K7 hyperacetylation, inducing conformational compaction and translocation to the intermembrane space. Acetylated NDUFA13 competitively engaged PHB2 through its coiled-coil domain, displacing PHB1 and disassembling prohibitin scaffolds. The acetylation-mimetic NDUFA13-K7Q induced cristae fragmentation in vitro, and cardiomyocyte-specific K7Q knock-in mice showed accelerated mortality and cristae loss under pressure overload, accompanied by impaired TCA cycle flux, defective fatty acid oxidation and selective depletion of polyunsaturated cardiolipins. These findings establish NDUFA13-K7 acetylation as a reversible switch converting bioenergetic failure into pathological cristae remodelling and metabolic reprogramming, highlighting therapeutic potential for targeted deacetylation.

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Nan, J., Yang, X., Lin, Y., Shen, J., Chen, H., Xu, Z., Ye, J., Wang, Y., Xiong, D., Ke, C., Zhu, L., Kong, X., Zhong, Z., Ren, T., Jiang, J., Wang, X., Wang, B., Zhao, D., Li, Z.-z., Shao, Z., Liu, B., He, X.. 2026-10-28. Acetylation of NDUFA13 at K7 Senses OXPHOS Dysfunction to Disrupt Prohibitin Scaffolds and Drive Cristae Remodelling in Heart Failure. https://doi.org/10.64898/2026.10.26.761921

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