Ca2+ dynamics in the mitochondria - state of the art

Abstract

The importance of [Ca²⁺] in the mitochondrial matrix, [Ca²⁺]_mito, had been proposed by early work of Carafoli and others [1], [2] and [3]. The key suggestion in the 1970s [4] was that regulatory [Ca²⁺]_mito played a role in controlling the rate of activation of tricarboxylic acid cycle dehydrogenases, important in the regulation of ATP production by the electron transport chain (ETC) during oxidative phosphorylation. This view is now established [5] and [6] and the key questions currently debated are to what extent do the mitochondria acquire and release Ca²⁺, and what impact do mitochondria have on the dynamic Ca²⁺ signal in the cardiac ventricular myocyte [7]. Although investigations of Ca²⁺ dynamics in mitochondria have been problematic, disparate and inconclusive, they have also been both provocative and exciting. A recent special issue of this journal presented contrasting perspectives on the speed, extent and mechanisms of changes in [Ca²⁺]_mito, and how these changes may influence cellular spatio-temporal [Ca²⁺]_i dynamics [8]. An audio discussion is also available online [9]. The uncertain nature of the signaling pathways is noted in Table 1 (see below) which shows mitochondrial proteins and processes that are of current focus and which remain contentious. Each of the “items” listed is largely unsettled, or is a “work in progress”. There may be advocates for opposing positions noted or recent discoveries that must still be tested at multiple levels by diverse laboratories. Currently, the first item, the mitochondrial sodium/calcium exchanger (NCLX) [10], appears the most solid with respect to the molecular identification and physiological function, whereas, the recently described candidates of the mitochondrial Ca²⁺ uniporter (MCU) [11] and [12] still need to be verified and broadly examined by the scientific community.

Fig. 1

Dynamic [Ca²⁺]_i signals bathe mitochondria. At the peak of a Ca²⁺ spark, the Z-disk end of an intermyofibrillar mitochondrion will be bathed by [Ca²⁺]_i at about 10 μM while the [Ca²⁺]_i at the mid-mitochondrion is about 500 nM. Data replotted from Williams et al 2011 and Sobie et al 2002 [45] and [46]; see text for more details.