Limonoid DDK restores mitochondrial redox homeostasis to alleviate metabolic dysfunction-associated steatohepatitis via promoting SDHA deacetylation and SDH complex activity

We identified succinate dehydrogenase subunit A (SDHA) as a direct functional target of the natural limonoid compound DDK. Using CETSA coupled with mass spectrometry (MS) and bio-layer interferometry (BLI), we demonstrate that DDK directly binds SDHA.

The mitochondrial-protecting and oxidative phosphorylation (OXPHOS)-recovering effects of limonoid compound DDK were abolished in SDHA-deficient hepatocytes, suggesting that SDHA is indispensable for DDK’s bioactivity. SDH activity decreased in the liver tissues of MASH murine models, while SDHA knockdown in hepatocytes further aggravated impaired OXPHOS activity and mitochondrial dysfunction. Mechanistically, DDK promoted complex II (SDH) assembly and enzymatic activity by reducing pathological acetylation of SDHA at lysine 335.