The mitochondrial membrane potential powers both ATP production and mitochondrial Ca2+ transient of mitochondrial Ca2+ permeation into the mitochondria via the mitochondrial Ca2+ uniporter MCU followed by Ca2+ efflux by by the 3Na+/Ca2+ exchanger, NCLX that was discovered by our group . In the first part of my talk I will describe a new strategy for controlling the mitochondrial membrane potential. We are using optogenetic channels for a light dependent control in mitochondrial l membrane potential . In the first part of my talk I will described the challenges of targeting these “optometabolic channels to mitochondria and of using them to study metabolic processes, Ca2+ signaling and physiological activities. The second part on my talk will focus on our studies of the mitochondrial NCLX. . I will first describe how by combining molecular control of NCLX activity with cytosolic or mitochondrial Ca2+ imaging we study the role of NCLX in cell models related to diabetes Parkinson (PD) or pain sensation. I will then describe the mode of NCLX regulation by PKA phosphorylation. Finally I will present new data linking phosphorylation of NCLX to allosteric regulation of NCLX by mitochondrial membrane potential and describe the physiological implication of this regulation on thermogeneration in brown fat.