Mitochondrial calcium transport: physiological and pathological relevance

Abstract

Since the initiation of work on mitochondrial Ca2+ transport in the early 1960s, the relationship between experimental observations and physiological function has often seemed enigmatic. Why, for example, should an organelle dedicated to the crucial task of producing approximately 95% of the cell's ATP sequester Ca2+, sometimes in preference to phosphorylating ADP? Why should there be two separate efflux mechanisms, the Na+ independent and the Na+ dependent, both thought until recently to be driven exclusively either directly or indirectly by the energy of the pH gradient? Does intramitochondrial free Ca2+ concentration control metabolism? Is there evidence for any separate function of the mitochondrial Ca2+ transport mechanisms under pathological conditions? What is the relationship between mitochondrial Ca2+ transport, the mitochondrial membrane permeability transition, and irreversible cell damage under pathological conditions? First, we review what is known about control of metabolism, evidence for a role for intramitochondrial Ca2+ in control of metabolism, the cellular conditions under which mitochondria are exposed to Ca2+, characteristics of the mitochondrial Ca2+ transport mechanisms including the permeability transition, and evidence for and against mitochondrial Ca2+ uptake in vivo. Then the questions listed above and others are addressed from the perspective of the characteristics of the mechanisms of mitochondrial Ca2+ transport.

Excitation-contraction coupling and mitochondrial energetics

“…In contrast, in the study of Kirichok et al [109], the potential across the inner mitochondrial membrane could be maintained by voltage-clamp, allowing Ca 2+ flux at much higher extra-and intramitochondrial [Ca 2+ ] than in mitochondrial suspensions or whole cells. This may explain the differences of K 0.5 and V max for mitochondrial Ca 2+ transport between those studies [76,77,109].…”

“…An important difference between the study by Kirichok et al [109] and previous studies [76,77] concerning ionic flux estimates is that in mitochondrial suspensions [76,77] or whole cardiac myocytes [222], dissipation of Δψ m due to Ca 2+ entry at very high extramitochondrial [Ca 2+ ] may reduce the driving force for further Ca 2+ uptake, leading to (pseudo-) lower transport rates that saturate at lower extramitochondrial [Ca 2+ ]. In contrast, in the study of Kirichok et al [109], the potential across the inner mitochondrial membrane could be maintained by voltage-clamp, allowing Ca 2+ flux at much higher extra-and intramitochondrial [Ca 2+ ] than in mitochondrial suspensions or whole cells.…”

“…1), driven by the large electrochemical gradient for Ca 2+ across the inner mitochondrial membrane (Δψ m ∼ −180 mV). From experiments on suspensions of isolated mitochondria, a half-maximal activation constant (K 0.5 ) of ∼10-20 µM Ca 2+ was calculated for mCU-mediated Ca 2+ transport, yielding a maximum Ca 2+ flux (V max ) of approximately 2·10 4 Ca 2+ s −1 for a single mCU molecule [76,77]. The mCU is inhibited by ruthenium red [124,138,157] or Ru360 [109,117,124], with the latter being more mCUselective than ruthenium red [124], which also inhibits SR Ca 2+ release via RyR2 [35].…”

“…Mn 2+ competes with Ca 2+ for the mCU [76,77] (although patch-clamp studies suggest that the selectivity of the mCU for Ca 2+ vs Mn 2+ is > 15-fold [109]) and can be taken up into mitochondria as well [26,33,69,76,77,222], where it may inhibit oxidative phosphorylation [70]. Thus, Mn 2+ could potentially reduce the rate of the mCU, on the one hand by competing with Ca 2+ , on the other hand by reducing Δψ m .…”

“…3B; [54,56,57,127,128]). As reviewed previously [76,77,79,129], Ca 2+ is taken up by mitochondria via a Ca 2+ uniporter (mCU; Fig. 1 Cardiac myocytes, in particular, display a highly organized juxtaposition of sarcolemma, SR and mitochondria (Fig.…”