SIRT3 deficiency triggers mitochondrial dysfunction-associated senescence to suppress colorectal cancer progression via SLC25A13 acetylation.

Authors

Wei Liu, Hongyao Li, Xuelan Ma, Yi Wang, Yuanyuan Yang, Zhiqi Peng, Yingjie Wang, Jin Zhang, Bo Liu, Ning Li

Published in

Oncogene. Oct 31, 2026. Epub Oct 31, 2026.

Abstract

Mitochondrial dysfunction is frequently well-known to induce mitochondrial dysfunction-associated senescence (MIDAS), a specialized form of cellular senescence marked by a distinct senescent phenotype. Sirtuin-3 (SIRT3) is a key regulator of mitochondrial function through its deacetylase activity, and emerging evidence highlights that its deficiency induces MIDAS in fibroblasts. However, the precise mechanism by which SIRT3 regulates MIDAS, as well as the role of MIDAS in tumorigenesis, remains incompletely understood. Here, we report that SIRT3 deficiency inhibits colorectal cancer (CRC) progression by inducing MIDAS. Mechanistically, SIRT3 deacetylates the mitochondrial carrier SLC25A13 at lysine 568. SIRT3 loss triggers K568 hyperacetylation, impairing SLC25A13 function and disrupting the malate-aspartate shuttle. This cascade reduces the cytosolic NAD⁺/NADH ratio, activating the AMPK-p53 axis to initiate MIDAS. Clinically, low levels of SLC25A13-K568 acetylation are associated with poor prognosis in human CRC. Furthermore, senolytic treatment selectively eliminates these senescent cells and suppresses tumor growth. Our findings unveil a SIRT3-SLC25A13 axis governing NAD⁺/NADH homeostasis and MIDAS, revealing a potential therapeutic strategy for CRC.

PMID:
42966746
Bibliographic data and abstract were imported from PubMed on 01 Nov 2026.

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