Calcium signaling in mitochondrial intermembrane space

Abstract

The mitochondrial intermembrane space (IMS) is a highly protected compartment, second only to the matrix. It is a crucial bridge, coordinating mitochondrial activities with cellular processes such as metabolites, protein, lipid, and ion exchange. This regulation influences signaling pathways for metabolic activities and cellular homeostasis. The IMS harbors various proteins critical for initiating apoptotic cascades and regulating reactive oxygen species production by controlling the respiratory chain. Calcium (Ca2+), a key intracellular secondary messenger, enter the mitochondrial matrix via the IMS, regulating mitochondrial bioenergetics, ATP production, modulating cell death pathways. IMS acts as a regulatory site for Ca2+ entry due to the presence of different Ca2+ sensors such as MICUs, solute carriers (SLCs); ion exchangers (LETM1/SCaMCs); S100A1, mitochondrial glycerol-3-phosphate dehydrogenase, and EFHD1, each with unique Ca2+ binding motifs and spatial localizations. This review primarily emphasizes the role of these IMS-localized Ca2+ sensors concerning their spatial localization, mechanism, and molecular functions. Additionally, we discuss how these sensors contribute to the progression and pathogenesis of various human health conditions and diseases.

Keywords: Ca2+ sensors; LETM1; MICU; SCaMs; SLC25A12/13; mitochondrial intermembrane space.

Figure 1.. Mitochondrial IMS localized Ca²⁺ sensors regulate Ca²⁺ homeostasis.

Elevated _cCa²⁺ levels lead to mitochondrial entry of Ca²⁺ via the outer mitochondrial membrane (OMM) embedded voltage-dependent anion channel (VDAC), which is freely selective for _cCa²⁺. However, once inside intermembrane space (IMS), _mCa²⁺ cannot freely cross the inner mitochondrial membrane (IMM). A distinct population of IMM localized, IMS facing Ca²⁺ sensors play significant role in transporting Ca²⁺ to the matrix. The mitochondrial calcium uniporter (mtCU) plays the most important role in transporting Ca²⁺ inside matrix. MICU1 is the main component of mtCU which regulates MCU channel opening and Ca²⁺ entry. MICU1 also interacts with MIC60, a component of the mitochondrial contact site and cristae organizing system (MICOS), helping to maintain mitochondrial ultrastructure. The solute carrier protein SLC25A23 also augments _mCa²⁺ uptake by interacting with MCU and MICU1. SLC25A12/13 are Ca²⁺-binding glutamate-aspartate transporters that act as critical regulators of the malate-aspartate shuttle. Solute carrier family members Ca²⁺ modulated carriers (sCaMCs) are other type of Ca²⁺-sensors that act as ADP/ATP transporter across the IMM. LETM1 functions as Ca²⁺/H⁺ or Ca²⁺/K⁺ antiporter across IMM, while mtGPD1 is a FAD-linked Ca²⁺ sensitive IMS protein that catalyzes glycerol-3-phosphate oxidation to dihydroxyacetone phosphate (DHAP), accompanied by enzyme-bound FAD reduction to FADH₂. S100A1 interacts with F1-ATpase in a Ca²⁺ dependent manner, increasing the generation of ATP in cardiomyocytes. EFHD1 is associated with mitoflash event involving random mitochondrial H₂O₂ generation. Once inside matrix, _mCa²⁺ can regulate activity of several TCA cycle enzymes including isocitrate dehydrogenase (IDH), α-ketoglutarate dehydrogenase (KDH) and pyruvate dehydrogenase (PDH).