Peilin Yu,Zhenming Liu,Xiafei Yu,Peiwu Ye,Huan Liu,Xiwen Xue,Lixin Yang,Zhongtang Li,Yang Wu,Cheng Fang,Yong Juan Zhao,Fan Yang,Jian Hong Luo,Lin-Hua Jiang,Liangren Zhang,Lihe Zhang,Wei Yang
Summary cADPR is a well-recognized signaling molecule by modulating the RyRs, but considerable debate exists regarding whether cADPR can bind to and gate the TRPM2 channel, which mediates oxidative stress signaling in diverse physiological and pathological processes. Here, we show that purified cADPR evoked TRPM2 channel currents in both whole-cell and cell-free single-channel recordings and specific binding of cADPR to the purified NUDT9-H domain of TRPM2 by surface plasmon resonance. Furthermore, by combining computational modeling with electrophysiological recordings, we show that the TRPM2 channels carrying point mutations at H1346, T1347, L1379, S1391, E1409, and L1484 possess distinct sensitivity profiles for ADPR and cADPR. These results clearly indicate cADPR is a bona fide activator at the TRPM2 channel and clearly delineate the structural basis for cADPR binding, which not only lead to a better understanding in the gating mechanism of TRPM2 channel but also shed light on a cADPR-induced RyRs-independent Ca 2+ signaling mechanism.
Cellular senescence is a stable cell cycle arrest program with important therapeutic implications in cancer, yet how metabolic perturbations are translated into redox-dependent senescence remains incompletely understood. Here, we identify triosephosphate isomerase 1 (TPI1) as a critical regulator of senescence in clear cell renal cell carcinoma (ccRCC) through a customized CRISPR-Cas9 metabolic screen. TPI1 depletion induces a robust senescence phenotype characterized by mitochondrial redox imbalance, DNA damage, and stable growth arrest. Mechanistically, loss of TPI1 leads to accumulation of dihydroxyacetone phosphate (DHAP), which engages a SARM1-dependent signaling pathway, resulting in increased cyclic ADP-ribose (cADPR) production and intracellular Ca 2+ release. This cADPR-Ca 2+ axis drives mitochondrial ROS (mtROS) generation, thereby promoting DNA damage and activation of the p53-p21 pathway to enforce senescence. Pharmacological or genetic attenuation of calcium signaling, or mitochondrial ROS partially rescues these phenotypes, indicating that calcium-dependent redox stress is required for senescence induction. Importantly, this metabolic–redox signaling cascade is conserved across multiple cancer types. Collectively, our findings define a previously unrecognized TPI1–SARM1–cADPR–Ca 2+ axis that links glycolytic metabolite accumulation to mitochondrial redox stress and cellular senescence, highlighting a metabolite-driven redox vulnerability that may be therapeutically exploitable in cancer.
危险品化学品经营许可证（带存储）