RT Journal Article
SR Electronic
T1 Calcium Homeostasis Modulator 2 Constitutes an ATP-regulation Pore in Mitochondria
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.09.30.615983
DO 10.1101/2024.09.30.615983
A1 Guo, Qian-Jin
A1 Hou, Tingting
A1 Xie, Wen-Jun
A1 Zhang, Jing-Ruo
A1 Ma, Xin-Lei
A1 Guo, Yingna
A1 Wang, Xiao-Ting
A1 Wang, Li-Peng
A1 Lu, Ming-Ao
A1 Wu, Zhaofa
A1 Wang, Hong-Guang
A1 Chen, Yi-Hang
A1 Li, Yu-Long
A1 Wang, Shi-Qiang
YR 2024
UL http://biorxiv.org/content/early/2024/10/01/2024.09.30.615983.abstract
AB Recent structural analyses showed that the calcium homeostasis modulator-2 (CALHM2) forms a mega channel, but its cellular location and endogenous function are yet unknown. We found that native CALHM2 resides on the mitochondrial inner membrane and constitutes an ATP-regulated ATP release channel. CALHM2 knockdown/knockout decreases cytosolic ATP concentration, and thereby compromises energy-sensitive processes, such as intracellular Ca2+ handling. However, CALHM2 loss-of-function elevates ATP concentration in the mitochondrial matrix, dephosphorylates key enzymes in the mammalian target of rapamycin (mTOR) pathway, and promotes longevity in CALHM2 knockout mice. These findings reveal that CALHM2 constitutes a novel regulator of mitochondrial metabolism, which may have important implications in aging and diseases.Competing Interest StatementThe authors have declared no competing interest.