Mitochondrial calcium homeostasis as potential target for mitochondrial medicine

Abstract

Mitochondria are crucial in different intracellular pathways of signal transduction. Mitochondria are capable of decoding a variety of extracellular stimuli into markedly different intracellular actions, ranging from energy production to cell death. The fine modulation of mitochondrial calcium (Ca(2+)) homeostasis plays a fundamental role in many of the processes involving this organelle. When mitochondrial Ca(2+) homeostasis is compromised, different pathological conditions can occur, depending on the cell type involved. Recent data have shed light on the molecular identity of the main proteins involved in the handling of mitochondrial Ca(2+) traffic, opening fascinating and ambitious new avenues for mitochondria-based pharmacological strategies.

Fig. 1

Mitochondrial physiology and mitochondrial Ca²⁺ handling. Ca²⁺ enters in the mitochondrial matrix via a low affinity uniporter (MCU) and through a high electronegative potential (− 180 mV). Extrusion of Ca²⁺ takes two major routes, one driven by the Na⁺/Ca²⁺ exchanger, and another pathway which involves H⁺–Ca²⁺ exchanger. In the matrix, Ca²⁺ stimulates the activity of three Ca²⁺-sensitive dehydrogenases of the Krebs cycle. The gradient across the inner membrane is important for the mitochondrial state and is established by the activity of the mitochondrial respiratory chain. VDAC: voltage-dependent anion channel, ANT: adenosine nucleoside transporter, HK: hexokinase, CD: cyclophilin D, CK: creatine kinase, BR: benzodiazepine receptor, PTP: permeability transition pore.

Fig. 2

Schematic representation of mitochondrial dysfunctions in some common disease. A. In pancreatic β cells, generalized reduction of mitochondrial Ca²⁺ uptake (due to reduced extracellular Ca²⁺ influx or Ca²⁺ release from stores) impairs Krebs cycle and electron transport chain (ETC) activity. Anomalous ROS production can generate mitochondrial DNA mutations, leading to further malfunctioning of ETC. The resulting impairment in ATP production brings to reduced β cell activity and reduced insulin release. B. Excessive mitochondrial Ca²⁺ uptake induces opening of PTP leading to well known toxic effects. Further excessive ion concentration impairs ETC efficiency promoting ROS generation with consequent lipid perodxation and enhancement the probability of PTP opening. C. Ca²⁺ overload induce cell death in neurons. In Alzheimer's disease the presence of β-amyloid leads to ROS generation in neurons, causing cytosolic Ca²⁺ accumulation by different mechanisms. This homeostasis deregulation brings to mitochondrial Ca²⁺ overload and PTP opening. Mitochondrial Ca²⁺ overload is also responsible for dopaminergic neurons death in Parkinson's disease. D. Neuronal severe dysfunctions can be generated by reduced mitochondrial Ca²⁺ uptake in mitochondrial primary diseases (MIDs). Mutations in mtDNA are able to affect ETC and mitochondrial membrane potential and ROS generation, leading to impaired ATP synthesis and reduced Ca²⁺ accumulation. Because of the Ca²⁺ dependency of some enzymes of Krebs cycle a positive feedback progressively reduced the ability of mitochondria to synthetize ATP affecting cell physiology and survival.