Mechanisms regulating mitochondrial Ca ²⁺ . The MCU is the primary protein responsible for Ca²⁺ uptake into the mitochondria. The energy for Ca²⁺ uptake is provided by the large negative membrane potential that is generated by the electron transport chain (ETC). The ETC is also responsible for generating an alkaline matrix pH. The inwardly directed proton gradient drives the efflux of a number of ions including Na⁺, K⁺, and Ca²⁺. In addition to CHE, Ca²⁺ efflux from the matrix occurs via a CHE. There are also data suggesting a role for Ca²⁺ entry via an electrogenic Ca²⁺/H⁺ exchanger, although this needs confirmation. Much of the mitochondrial Ca²⁺ is buffered within Ca-P granules. The phosphate enters the mitochondria on the phosphate carrier (PiC) in exchange for proton.