Outstanding questions regarding the permeation,selectivity, and regulation of the mitochondrial calcium uniporter

The recent discovery of genes encoding the mitochondrial calcium (Ca²⁺) uniporter has revealed new opportunities for studying how abnormal Ca²⁺ signals cause disease. Ca²⁺ transport across the mitochondrial inner membrane is highly regulated, and the uniporter is the channel that acts as a major portal for Ca²⁺ influx. Low amounts of mitochondrial Ca²⁺ can boost ATP synthesis, but excess amounts, such as following cytoplasmic Ca²⁺ overload in heart failure, triggers mitochondrial failure and cell death. In fact, precisely because mitochondrial Ca²⁺ transport is so tightly regulated, a fundamental understanding of how the uniporter functions is necessary. Two key uniporter features allow Ca²⁺ influx without mitochondrial damage during normal physiology. First, the channel is significantly more selective than other known Ca²⁺ channels. This prevents the permeation of other ions and uncoupling of the electrochemical gradient. Second, the uniporter becomes active at only high Ca²⁺ concentrations, preventing a resting leak of cytoplasmic Ca²⁺ itself. Now possessing the identities of the various proteins forming the uniporter, we can proceed with efforts to define the molecular determinants of permeation, selectivity and Ca²⁺-regulation.