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

The recent discovery of genes encoding the mitochondrial calcium (Ca(2+)) uniporter has revealed new opportunities for studying how abnormal Ca(2+) signals cause disease. Ca(2+) transport across the mitochondrial inner membrane is highly regulated, and the uniporter is the channel that acts as a major portal for Ca(2+) influx. Low amounts of mitochondrial Ca(2+) can boost ATP synthesis, but excess amounts, such as following cytoplasmic Ca(2+) overload in heart failure, triggers mitochondrial failure and cell death. In fact, precisely because mitochondrial Ca(2+) transport is so tightly regulated, a fundamental understanding of how the uniporter functions is necessary. Two key uniporter features allow Ca(2+) influx without mitochondrial damage during normal physiology. First, the channel is significantly more selective than other known Ca(2+) channels. This prevents the permeation of other ions and uncoupling of the electrochemical gradient. Second, the uniporter becomes active at only high Ca(2+) concentrations, preventing a resting leak of cytoplasmic Ca(2+) 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 Ca(2+)-regulation.