Mitochondrial Ca(2+) and neurodegeneration

Abstract

Mitochondria are essential for ensuring numerous fundamental physiological processes such as cellular energy, redox balance, modulation of Ca(2+) signaling and important biosynthetic pathways. They also govern the cell fate by participating in the apoptosis pathway. The mitochondrial shape, volume, number and distribution within the cells are strictly controlled. The regulation of these parameters has an impact on mitochondrial function, especially in the central nervous system, where trafficking of mitochondria is critical to their strategic intracellular distribution, presumably according to local energy demands. Thus, the maintenance of a healthy mitochondrial population is essential to avoid the impairment of the processes they regulate: for this purpose, cells have developed mechanisms involving a complex system of quality control to remove damaged mitochondria, or to renew them. Defects of these processes impair mitochondrial function and lead to disordered cell function, i.e., to a disease condition. Given the standard role of mitochondria in all cells, it might be expected that their dysfunction would give rise to similar defects in all tissues. However, damaged mitochondrial function has pleiotropic effects in multicellular organisms, resulting in diverse pathological conditions, ranging from cardiac and brain ischemia, to skeletal muscle myopathies to neurodegenerative diseases. In this review, we will focus on the relationship between mitochondrial (and cellular) derangements and Ca(2+) dysregulation in neurodegenerative diseases, emphasizing the evidence obtained in genetic models. Common patterns, that recognize the derangement of Ca(2+) and energy control as a causative factor, have been identified: advances in the understanding of the molecular regulation of Ca(2+) homeostasis, and on the ways in which it could become perturbed in neurological disorders, may lead to the development of therapeutic strategies that modulate neuronal Ca(2+) signaling.

Fig. 1

The main players in mitochondrial Ca²⁺ transport. Ca²⁺ flows into the cytoplasm upon cell stimulation and the opening of the inositol trisphosphate receptors (InsP₃R), the ryanodine receptors (RyR) at the ER/SR membranes and/or of the plasma membrane associated voltage (VOC), receptor (ROC) and store (SOC) operated calcium channels. The generation of localized high Ca²⁺ concentration microdomains drives Ca²⁺ into the mitochondrial matrix via the mitochondria Ca²⁺ uniporter (MCU), this action being potentiated by the voltage-dependent anion channel (VDAC) that, through GRP75, enhanced the ER Ca²⁺ transfer. MICU1 is a MCU associated protein that acts as MCU regulator. The efflux mechanism depends on the activity of the H⁺/Ca²⁺ and the Na⁺/Ca²⁺ exchangers. Increased mitochondrial Ca²⁺ concentration stimulates TCA cycle enzymes generating NADH and increasing ATP synthesis and ROS production. Sustained increases in mitochondrial Ca²⁺ concentration sensitize mitochondria to permeability transition pore (mPTP) opening with consequent release of cytochrome c (cyt c) and induction of apoptosis. Cytosolic Ca²⁺ clearance depends on the activity of the plasma membrane Ca²⁺ ATPase (PMCA), of the plasma membrane Na⁺/Ca²⁺ exchanger (NCX) and of the ER/SR Ca²⁺ATPase (SERCA). ER, Endoplasmic reticulum; OMM, outer mitochondrial membrane; IMS, intermembrane mitochondrial space; IMM, inner mitochondrial membrane.

Fig. 2

Mitochondrial dysfunctions and Ca²⁺ homeostasis in AD. Peptide β-amyloid (Aβ) oligomers affect mitochondrial functionality either by increasing cytosolic Ca²⁺ concentration through a pore-forming mechanism at the plasma membrane and/or by enhancing ER Ca²⁺ release. Possible mitochondrial Aβ accumulation impairs mitochondrial energy metabolism, leading to mitochondrial oxidative damage. Aβ may sensitize mPTP opening by interacting with cyclophilin D (CypD). FAD-linked mutant presenilins (PSs) may alter the expression/sensitivity of ER Ca²⁺ release channels (RyR and InsP₃R) leading to an exaggerated ER Ca²⁺ release and abnormal mitochondrial Ca²⁺ uptake. A reduction in SERCA activity has also been described. Wild-type PSs, but not the FAD mutants, were reported to form Ca²⁺ permeable leak channels in the ER. PSs have also been found in mitochondria.

Fig. 3

Mitochondrial dysfunctions and Ca²⁺ homeostasis in PD. α-syn monomers impair complex I and complex III activity, while oligomeric α-syn has been shown to potentiate intracellular Ca²⁺ influx through the VOC. DJ-1 scavenges mitochondrial ROS and sustain complex I activity. PINK1, possibly, modulates the activity of the mitochondrial Na⁺/Ca²⁺ exchanger and/or of the MCU. Additionally, together with parkin, it acts as a sensor to direct damaged mitochondria to the mitophagy process. Parkin attenuates protein misfolding and may protect against apoptotic stimuli, by preventing the opening of mPTP.

Fig. 4

Mitochondrial dysfunctions and Ca²⁺ homeostasis in ALS and HD. Mutant SOD1 in ALS and mutant Htt in HD enhance intracellular Ca²⁺ permeability, impair mitochondrial membrane potential and increase the susceptibility to mitochondrial Ca²⁺ overload, thus inducing mPTP opening, the release of cytochrome c (cyt c) and apoptosis. Mutant Htt increases ER Ca²⁺ release by acting on the InsP₃R. Mutant VAPD (a protein found associated with mutant forms of ALS) enhances ER-mitochondria tethering, leading to an augmented mitochondrial Ca²⁺ uptake. Increased mitochondrial Ca²⁺ concentration, in turn, stimulates TCA cycle enzymes generating NADH and increasing ATP synthesis and ROS production.