Mitochondrial calcium transport in the heart: physiological and pathological roles.
That intramitochondrial free calcium ([Ca(2+)](m)) plays various critical roles in both normal physiological and pathological conditions in the heart is now well-accepted, and evidenced by the interest and work in this area of the last two decades. However, controversies remain; such as the existence of beat-to-beat mitochondrial Ca(2+) transients, role of [Ca(2+)](m) in modulating whole-cell Ca(2+) signalling, whether or not [Ca(2+)](m) is critical for increases in ATP supply upon increased demand, and its role in cell death by both necrosis and apoptosis, especially in formation of the mitochondrial permeability transition pore and in ischaemic preconditioning. Neither is there a consensus as to whether inhibiting the Ca(2+) influx or efflux pathways--the Ca(2+) uniporter (MCU) and Na(+)/Ca(2+)-excahnger (mNCX), respectively--is cardioprotective, largely due to lack of specific inhibitors of these transporters. Ruthenium red, Ru360, clonazepam and CGP37157 are all very effective in isolated mitochondria, but reports of their effectiveness in whole cell and heart studies vary considerably, which partly accounts for the lack of a consensus on protective effects. The purification and cloning of the transporters, and development of more specific inhibitors, would produce a step-change in our understanding of the role of these apparently critical but still elusive proteins. However, developments in fluorescent indicators, proteins and imaging technology have meant that [Ca(2+)](m) can now be measured reasonably specifically in intact cells and hearts, and interactions of the mitochondrial Ca(2+) transporters with those of the sarcolemma or sarcoplasmic reticulum are being revealed. This has gone a long way to bringing the transporters to the forefront of cardiac research.
Griffiths
Elinor J
EJ
Department of Biochemistry, School of Medical Sciences, and Bristol Heart Institute, University of Bristol, Bristol, UK. Elinor.Griffiths@bris.ac.uk
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D006321:Heart; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism*; D008954:Models, Biological; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
D019831:Sodium-Calcium Exchanger; D002118:Calcium