Mitochondrial Calcium Governed By Cytoplasmic Nad+ Regulates Energy Production
The ability of cells to sense energy status and coordinate mitochondrial metabolism for energy homeostasis is critical for organismal development and survival. Mitochondrial calcium signaling has emerged as a key mediator of mitochondrial bioenergetics. Currently there is a significant knowledge gap regarding how mitochondrial calcium is adjusted to cellular energetics. Here, we report mitochondrial calcium in C. elegans muscle cells progressively decline during development and is modulated by cytosolic NAD+. We find that increasing cytoplasmic NAD+ level reduces mitochondrial calcium by promoting mitochondrial matrix calcium efflux. Examining mitochondrial calcium dynamics throughout development reveals a link between mitochondrial calcium handling and mitochondrial content. Intriguingly, decreased mitochondrial calcium with loss of mitochondrial calcium uniporter (MCU-1) also increases mitochondrial content and thus augments ATP production. Collectively, our data uncover a previously unidentified non-oxidative role of NAD+ in regulating mitochondrial calcium handling and reveal a novel mechanism of mitochondrial metabolic adaptation to cellular energy demands.