SR and mitochondria: calcium cross-talk between kissing cousins.
The processes of excitation-contraction coupling in cardiac myocytes require enormous amounts of energy in the form of ATP, which is produced by oxidative phosphorylation in mitochondria. Due to the constantly varying workloads of the heart, efficient matching of energy supply to demand is a requisite for proper heart function. Ca(2+) is taken up by mitochondria via the mitochondrial Ca(2+) uniporter (MCU) where it stimulates key dehydrogenases of the Krebs cycle to match regeneration of NADH to its oxidation by the respiratory chain. The kinetics of mitochondrial Ca(2+) uptake, however, remain controversial due to the low Ca(2+) sensitivity of the MCU. Here, we review the evidence for the existence of a "mitochondrial Ca(2+) microdomain", in which the close association of the sarcoplasmic reticulum (SR) to mitochondria provides "hot spots" of very high Ca(2+) concentrations in the vicinity of mitochondria, sufficient to overcome the low Ca(2+) affinity of the MCU. Mitofusins 1 and 2 play redundant roles in regulating mitochondrial dynamics by controlling fusion of mitochondria with each other. Recent work revealed a unique role for mitofusin 2 in tethering mitochondria to the sarco-/endoplasmic reticulum in various cell types, including cardiac myocytes. Disruption of SR-mitochondrial Ca(2+) cross talk in heart failure through spatial and ionic alterations may give rise to energetic deficit and oxidative stress, two factors believed to play causal roles in the progression of the disease. On the other hand, excessive mitochondrial Ca(2+) uptake can trigger programmed necrosis, substantiating the ambiguity of the close interplay between these cousin organelles in health and disease. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".
Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. gdorn@dom.wustl.edu
Gerald W
GW
Dorn
Christoph
C
Maack
D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D024101:Mitochondrial Proteins