Mitochondrial Ca²⁺ as a Key Regulator of Mitochondrial Activities

Abstract

Mitochondria play a central role in cell biology, not only as producers of ATP but also as regulators of the Ca²⁺ signal. The translocation by respiratory chain protein complexes of H⁺ across the ion-impermeable inner membrane generates a very large H⁺ electrochemical gradient that can be employed not only by the H⁺ ATPase to run the endoergonic reaction of ADP phosphorylation, but also to accumulate cations into the matrix. Mitochondria can rapidly take up Ca²⁺ through an electrogenic pathway, the uniporter, that acts to equilibrate Ca²⁺ with its electrochemical gradient, and thus accumulates the cation into the matrix, and they can release it through two exchangers (with H⁺ and Na⁺, mostly expressed in non-excitable and excitable cells, respectively), that utilize the electrochemical gradient of the monovalent cations to prevent the attainment of electrical equilibrium.

The uniporter, due to its low Ca²⁺ affinity, demands high local Ca²⁺ concentrations to work. In different cell systems these high Ca²⁺ concentration microdomains are generated, upon cell stimulation, in proximity of the plasma membrane and the sarco/endoplasmic reticulum Ca²⁺ channels.

Recent work has revealed the central role of mitochondria in signal transduction pathways: evidence is accumulating that, by taking up Ca²⁺, they not only modulate mitochondrial activities but also tune the cytosolic Ca²⁺ signals and their related functions. This review analyses recent developments in the area of mitochondrial Ca²⁺ signalling and attempts to summarize cell physiology aspects of the mitochondrial Ca²⁺ transport machinery.