Review articleMitochondrial calcium transport in the heart: Physiological and pathological roles
Introduction
Intramitochondrial free [Ca2+] ([Ca2+]m) is now recognised as having several important roles in the heart, under both physiological and pathological conditions; for example in the regulation of energy production, in modulating whole-cell Ca2+ signalling, and in the transition from reversible to irreversible injury during ischaemia–reperfusion, especially by formation of the mitochondrial permeability transition pore (MPTP). There has been a resurgence of interest in [Ca2+]m over the last two decades, sparked by development of targeted probes for measuring [Ca2+]m in living cells, and which has continued with the refinement of these probes and of imaging techniques to visualise [Ca2+] in various subcellular compartments, including mitochondria. The major pathways for mitochondrial Ca2+ transport in the heart are the Ca2+-uniporter (MCU) for Ca2+ influx and the mitochondrial Na+/Ca2+ exchanger (mNCX) for Ca2+ efflux. However, a continuing impediment to progression of research in this field is that the mitochondrial Ca2+ transport proteins have not been purified or cloned, and that use of the current inhibitors of these pathways is problematic in living cells, especially cardiomyocytes.
In this review I will summarise the development of theories on the role of [Ca2+]m in ATP production and Ca2+ signalling from historical studies through to present day controversies, including techniques for measuring [Ca2+]m. I will also discuss the role of [Ca2+]m in ischaemia–reperfusion injury in the heart, and whether the mitochondrial Ca2+ transporters are a realistic target for protective strategies; I will not describe the role of the MPTP apoptosis or necrosis in any detail as it is covered by other articles in this issue and in recent reviews [1], [2], [3].
Section snippets
Properties of the transporters
Ca2+ uptake by mitochondria was first described in the early 1960s in isolated kidney mitochondria as an energy dependent process, the energy coming from respiration [4], [5]. Large amounts of Ca2+ can be taken up by mitochondria together with inorganic phosphate (Pi) [6] and at levels above about 2 μM [Ca2+]m form an osmotically inactive calcium phosphate salt [7]. The nature of the calcium phosphate complex, and its low solubility in the mitochondrial matrix compared with that in solutions
Fluorescent and luminescent probes
Research into mitochondrial Ca2+ signalling was given a boost with the development in 1992 of a technique for measuring [Ca2+]m in living cells using the photoprotein aequorin targeted to mitochondria [54]. This, together with the continuing development of fluorescent indicators [55] and more recently genetically encoded fluorescent probes [56] has sparked a great deal of work and interest, not only in the role of [Ca2+]m as a regulator of metabolism, but also its role in controlling whole-cell
Evidence for beat-to-beat mitochondrial Ca2+ transients
In simple terms, excitation–contraction (EC) coupling in the heart occurs by depolarisation of the cell membrane (sarcolemma) causing L-type Ca2+-channels to open that then allow a small amount of Ca2+ into the cell. This triggers a much larger release of Ca2+ from the SR via the RyR – calcium-induced calcium release – that activates contractile proteins in a process that consumes ATP. Relaxation is initiated by Ca2+ reuptake back into the SR via the sarcoplasmic/endoplasmic reticulum ATPase
Activation of mitochondrial enzymes by [Ca2+]m
Oxidative phosphorylation in mitochondria provides most of the ATP in nearly all cell types, and accounts for over 90% of ATP production in the heart[98]. It was originally proposed that changes in the ADP/ATP ratio were the main regulator of ATP synthesis, and this was demonstrated in isolated mitochondria [99]. However, the role of a drop in ATP and increase in ADP as the trigger for stimulating ATP synthesis in vivo had to be re-evaluated when studies demonstrated that high energy phosphate
Mitochondrial Ca2+ — protective or harmful?
Mitochondria have the capacity to take up huge amounts of Ca2+[13], [14] and thus could potentially remove toxic levels of Ca2+ from the cytosol. Unfortunately, such accumulation of Ca2+ can eventually damage mitochondria both by competing for ATP production and more importantly by inducing the mitochondrial permeability transition pore (MPTP). It has been known for many years that Ca2+-induced mitochondrial dysfunction during ischaemia is associated with the transition from reversible to
Therapeutic implications
As well as the possible benefits of modulating [Ca2+]m during ischaemia/reperfusion injury discussed above, there is evidence that both RuR and Ru360 can reduce ventricular fibrillation (VF): In a pacing-induced model of VF in the isolated rat heart, perfusion with RuR (5 μM), or Ru360 (10 μM), resulted in conversion of VF to ventricular tachycardia (VT) [185]. This is potentially beneficial since VT commonly occurs before VF, and sudden cardiac death [186].
However, the benzodiazepines like
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