Ca(2+) transfer from the ER to mitochondria: when, how and why

Abstract

The heterogenous subcellular distribution of a wide array of channels, pumps and exchangers allows extracellular stimuli to induce increases in cytoplasmic Ca(2+) concentration ([Ca(2+)]c) with highly defined spatial and temporal patterns, that in turn induce specific cellular responses (e.g. contraction, secretion, proliferation or cell death). In this extreme complexity, the role of mitochondria was considered marginal, till the direct measurement with targeted indicators allowed to appreciate that rapid and large increases of the [Ca(2+)] in the mitochondrial matrix ([Ca(2+)]m) invariably follow the cytosolic rises. Given the low affinity of the mitochondrial Ca(2+) transporters, the close proximity to the endoplasmic reticulum (ER) Ca(2+)-releasing channels was shown to be responsible for the prompt responsiveness of mitochondria. In this review, we will summarize the current knowledge of: i) the mitochondrial and ER Ca(2+) channels mediating the ion transfer, ii) the structural and molecular foundations of the signaling contacts between the two organelles, iii) the functional consequences of the [Ca(2+)]m increases, and iv) the effects of oncogene-mediated signals on mitochondrial Ca(2+) homeostasis. Despite the rapid progress carried out in the latest years, a deeper molecular understanding is still needed to unlock the secrets of Ca(2+) signaling machinery.

Figure 1

(A) Schematical representation of mitochondria-ER contact sites and Ca²⁺ handling. Agonist stimulation induces IP₃ synthesis and consequently opening of IP₃R channel, which causes Ca²⁺ redistribution. SERCA, sercoplasmic/endoplasmic calcium ATPase; VDAC, voltage dependent anion channel; MCU, mitochondrial calcium uniporter; IP₃R, IP₃ receptor; (B) Combined 3D imaging of mitochondria and ER in a HeLa cell transiently expressing mtBFP(Y66H, Y145F) and erGFP(S65T) (5). (C) Rappresentative traces of ER and mitochondrial calcium response during agonist stimulation measured using specifically trageted aequorins.

Figure 2

Anti-apoptotic proteins Bcl-2 and Akt affect ER calcium homeostasis by differential mechanisms. (A) Bcl-2 overexpression increases the Ca²⁺ leak, while leaving Ca²⁺ accumulation unaffected, hence reducing the steady-state [Ca²⁺] levels. (B) Akt hyper-activation induces a decrease in ER Ca²⁺ release, probably through phosphorylation of IP₃R. As a direct consequence, the [Ca²⁺] increases caused by IP3-generating agonists were reduced in amplitude in both cytosol and mitochondria. Kinetics and [Ca²⁺] during agonist stimulation measured by ER targeted aequorin in Bcl-2 overexpression or AKT hyper-activation conditions, are shown in the respective panels.