Work

Ginsenoside Rg5 targets the KAT8-CISD2 axis to maintain mitochondrial homeostasis and antagonize senescence

Year: 2026

Type: article

Abstract: BackgroundMitochondrial dysfunction drives cellular senescence. CISD2, an outer mitochondrial membrane protein and longevity gene, declines with age, but the regulatory role of its post-translational modifications (PTMs) remains unclear. This study investigates how acetylation stabilizes CISD2 and explores ginsenoside Rg5’s anti-aging mechanism via the KAT8-CISD2 axis.MethodsAcetylomics (SILAC-MS) identified KAT8/MSL complex substrates. Co-IP, GST pull-down, and in vitro KAT assays validated KAT8-CISD2 interaction and acetylation. Cycloheximide chase, and ubiquitination assays determined acetylation’s role in CISD2 stability. Mitochondrial function (JC-1, DCFH-DA, mtDNA, ATP) and senescence (SA-β-gal, EdU, CCK8) were assessed in senescence cells and C. elegans (via CISD-1/MYS-2 RNAi). Cellular thermal shift assay (CETSA) and Rg5-PEGA pull-down confirmed Rg5-KAT8 binding.ResultsIn this study, we identified for the first time that the KAT8/MSL complex acetylates the K74 site of CISD2, thereby blocking STUB1-mediated ubiquitination and degradation at the K105 site. We demonstrated that acetylation of CISD2 K74 maintains mitochondrial homeostasis and enhances cellular resistance to oxidative stress and aging. In Caenorhabditis elegans, co-knockdown of MYS-2 and CISD-1 exacerbates mitochondrial defects and shortens lifespan. Ginsenoside Rg5 directly binds to KAT8, promoting acetylation of CISD2 at the K74 site, maintaining mitochondrial homeostasis, and alleviating aging phenomena in cells and nematodes.ConclusionThis study reveals that KAT8-mediated acetylation of CISD2 K74 maintains mitochondrial homeostasis by inhibiting ubiquitin-mediated degradation, which is a key mechanism in counteracting senescence. Ginsenoside Rg5, as a KAT8 agonist, targets and activates this pathway, providing a new strategy for anti-aging intervention.

Source: Phytomedicine

DOI: 10.1016/j.phymed.2026.157923