Mitochondrial Ca2+ uptake: tortoise or hare?

Abstract

Mitochondria are equipped with an efficient machinery for Ca(2+) uptake and extrusion and are capable of storing large amounts of Ca(2+). Furthermore, key steps of mitochondrial metabolism (ATP production) are Ca(2+)-dependent. In the field of cardiac physiology and pathophysiology, two main questions have dominated the thinking about mitochondrial function in the heart: 1) how does mitochondrial Ca(2+) buffering shape cytosolic Ca(2+) levels and affect excitation-contraction coupling, particularly the Ca(2+) transient, on a beat-to-beat basis, and 2) how does mitochondrial Ca(2+) homeostasis influence cardiac energy metabolism. To answer these questions, a thorough understanding of the kinetics of mitochondrial Ca(2+) transport and buffer capacity is required. Here, we summarize the role of mitochondrial Ca(2+) signaling in the heart, discuss the evidence either supporting or arguing against the idea that Ca(2+) can be taken up rapidly by mitochondria during excitation-contraction coupling and highlight some interesting new areas for further investigation.

Figure 1

Left panel: Transmission electron micrograph of bat myocardium illustrating close juxtaposition of junctional SR (jsr) Ca²⁺ release sites at the t-tubules (t) and the mitochondria (Mito) (Porter KR. Mitochondria and transverse tubules of bat heart. ASCB Image & Video Library. August 2006: FND-10. Available at: http://cellimages.ascb.org/u?/p4041coll12,56. All rights reserved. Reprinted under license from The American Society for Cell Biology). Right panel: Schematic representation of the key components of excitation-contraction-bioenergetic coupling. Arguing in favor of a rapid component of Ca²⁺ uptake, mitochondria are in close proximity to the SR junction containing L-type Ca²⁺ channels (L) and ryanodine receptors (RyR), which could drive fast uptake due to a large local Ca²⁺ gradient, despite a relatively high Km for Ca²⁺ uptake via the mitochondrial uniporter (mCU). Slower Ca²⁺ extrusion from the mitochondria via the mitochondrial Na⁺/Ca²⁺ exchanger (NCE) results in Ca²⁺ accumulation during rapid pacing. The fast Ca²⁺ signals may be required to provide rapid compensation for increased metabolic demand (and NADH oxidation) during high workloads through the activation of tricarboxylic acid (TCA) cycle dehydrogenases.