title: Outstanding questions regarding the permeation, selectivity, and regulation of the mitochondrial calcium uniporter.
abstract: 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.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, United States; Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.
authors.forename: Dipayan
authors.initials: D
authors.lastname: Chaudhuri
authors.affiliation: Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States. Electronic address: dclapham@enders.tch.harvard.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
mesh_terms: D017920:Antiporters / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000502:physiology
chemical_list: C086357:ATP-Mg-Pi carrier proteins, mitochondria; D017920:Antiporters; D015220:Calcium Channels; D024101:Mitochondrial Proteins; C585180:SMDT1 protein, human; C034703:mitochondrial calcium uniporter; D002118:Calcium