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

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.