Enjoy the Trip: Calcium in Mitochondria Back and Forth

Abstract

In the last 5 years, most of the molecules that control mitochondrial Ca(2+) homeostasis have been finally identified. Mitochondrial Ca(2+) uptake is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, a macromolecular structure that guarantees Ca(2+) accumulation inside mitochondrial matrix upon increases in cytosolic Ca(2+). Conversely, Ca(2+) release is under the control of the Na(+)/Ca(2+) exchanger, encoded by the NCLX gene, and of a H(+)/Ca(2+) antiporter, whose identity is still debated. The low affinity of the MCU complex, coupled to the activity of the efflux systems, protects cells from continuous futile cycles of Ca(2+) across the inner mitochondrial membrane and consequent massive energy dissipation. In this review, we discuss the basic principles that govern mitochondrial Ca(2+) homeostasis and the methods used to investigate the dynamics of Ca(2+) concentration within the organelles. We discuss the functional and structural role of the different molecules involved in mitochondrial Ca(2+) handling and their pathophysiological role.

Mechanisms of modulation of brain microvascular endothelial cells function by thrombin

“…A local increase in cytosolic Ca 2+ concentration, [Ca 2+ ] i , is buffered by mitochondrial Ca 2+ uptake (De Stefani et al, 2016) . Previous reports indicate that IP 3 -mediated increase in [Ca 2+ ] i , may be transmitted to the mitochondria, increasing mitochondrial Ca 2+ and bioenergetics (Hajnoczky et al, 1995).…”

Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca 2+ Signals is Controlled by the Stoichiometry of MICU1/2 and MCU

“…Tissue-specific differences in the Ca 2+ uptake kinetics have been noted for some time and attributed to tissue-specific alternative Ca 2+ uptake mechanisms. These mechanisms either had a phenomenological definition, such as rapid uptake mode, or were linked to ryanodine receptors or uncoupling proteins (Buntinas et al, 2001;De Stefani et al, 2016). Recently, comparison of I MiCa in different tissues revealed great differences in the current density (Fieni et al, 2012).…”

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

“…This diversity is the direct consequence of a tightly regulated Ca 2+ signaling toolkit that characterizes each specific cell and guarantees the realization of precise cellular events1–3. Mitochondria are active players in the regulation of cellular Ca 2+ dynamics thanks to dedicated molecular machineries that control Ca 2+ fluxes in and out organelle matrix4. Compartmentalization of Ca 2+ signals on one hand allows the completion of organelle-specific functions and on the other provides a physical buffer that can potentially shape cytosolic Ca 2+ waves, both locally and globally5–7.…”