Acetylation of NDUFA13 at K7 Senses OXPHOS Dysfunction to Disrupt Prohibitin Scaffolds and Drive Cristae Remodelling in Heart Failure
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.
Authors
- Zhehua Shao (ORCID: https://orcid.org/0000-0003-2719-950X)
- Tanchen Ren (ORCID: https://orcid.org/0000-0002-3382-7042)
- Zhiwei Zhong (ORCID: https://orcid.org/0000-0001-8598-961X)
- Binben Wang
- 刘滨晨
- Xuwen Wang (ORCID: https://orcid.org/0000-0003-3022-6513)
- Duoduo Zhao (ORCID: https://orcid.org/0000-0002-7602-3597)
- Changle Ke
- Lianlian Zhu (ORCID: https://orcid.org/0000-0002-2318-2279)
- Jinliang Nan (ORCID: https://orcid.org/0000-0003-0986-7877)
- Danyang Xiong (ORCID: https://orcid.org/0000-0002-0911-1888)
- Jian Shen (ORCID: https://orcid.org/0000-0002-7769-6013)
- Xiangmin Kong
- Zhengzheng Li (ORCID: https://orcid.org/0000-0003-0613-6999)
- Xinnuo Yang
- Yinuo Lin (ORCID: https://orcid.org/0000-0002-4475-3667)
- Hongpeng Chen
- Xiao He
- Zihan Xu
- Yaping Wang
- Jun Jiang
- Jian Ye
Institutions
- Wenzhou Medical University (CN)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- First Affiliated Hospital Zhejiang University (CN)
- East China Normal University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-10-28
- DOI
- https://doi.org/10.64898/2026.10.26.761921
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- preprint
Funders
- National Natural Science Foundation of China
- Zhejiang University
- Wenzhou Municipal Science and Technology Bureau
- National Science and Technology Major Project
- Natural Science Foundation of Zhejiang Province