PT  - JOURNAL ARTICLE
AU  - Guo, Qian-Jin
AU  - Hou, Tingting
AU  - Xie, Wen-Jun
AU  - Zhang, Jing-Ruo
AU  - Ma, Xin-Lei
AU  - Guo, Yingna
AU  - Wang, Xiao-Ting
AU  - Wang, Li-Peng
AU  - Lu, Ming-Ao
AU  - Wu, Zhaofa
AU  - Wang, Hong-Guang
AU  - Chen, Yi-Hang
AU  - Li, Yu-Long
AU  - Wang, Shi-Qiang
TI  - Calcium Homeostasis Modulator 2 Constitutes an ATP-regulation Pore in Mitochondria
AID  - 10.1101/2024.09.30.615983
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.09.30.615983
4099  - http://biorxiv.org/content/early/2024/10/01/2024.09.30.615983.short
4100  - http://biorxiv.org/content/early/2024/10/01/2024.09.30.615983.full
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.