Mitochondrial calcium plays a critical role in cellular energy production. The molecular machineries that control mitochondrial calcium transient have been identified. However, the metabolic regulation of mitochondrial calcium is less understood. In this thesis, I used C. elegans as a model organism and found cytosolic NAD+ was a regulatory mechanism for mitochondrial calcium homeostasis. NAD+ augmentation decreased mitochondrial calcium. In addition, mitochondrial calcium feedback modulated NAD+ content. Such mechanism generated a feedback circuit that contributed to both mitochondrial calcium and bioenergetics homeostasis, which was important for cellular energy homeostasis and cell health.