Mitochondria, calcium and cell death: a deadly triad in neurodegeneration

Abstract

Mitochondrial Ca(2+) accumulation is a tightly controlled process, in turn regulating functions as diverse as aerobic metabolism and induction of cell death. The link between Ca(2+) (dys)regulation, mitochondria and cellular derangement is particularly evident in neurodegenerative disorders, in which genetic models and environmental factors allowed to identify common traits in the pathogenic routes. We will here summarize: i) the current view of mechanisms and functions of mitochondrial Ca(2+) homeostasis, ii) the basic principles of organelle Ca(2+) transport, iii) the role of Ca(2+) in neuronal cell death, and iv) the new information on the pathogenesis of Alzheimer's, Huntington's and Parkinson's diseases, highlighting the role of Ca(2+) and mitochondria.

Figures

Fig. 1

Schematic map of mitochondrial Ca2+ transporters. Mitochondria accumulate Ca2+ in the matrix via an electrogenic Ca2+ uniporter (MCU) that acts to equilibrate Ca2+ according the electrochemical gradient generated by the respiratory chain (ETC). Voltage Dependent Anion Channel (VDAC) controls the Ca2+ diffusion through the outer mitochondrial membrane (OMM), thus facilitating mitochondrial Ca2+ accumulation. As to the efflux pathways, a Na+/Ca2+ and a H+/Ca2+ exchangers have been shown to operate. The permeability transition pore (PTP) opening plays different roles: its brief opening could allow rapid Ca2+ release, but its long-lasting openings (potentiated by apoptotic stimuli and Ca2+ itself) could trigger cell death process. IMS, intermembrane space; IMM, inner mitochondrial membrane.

Fig. 2

Presenilins (PSs), Amyloid Precursor Protein (APP) and peptide β-amyloid (Aβ) can affect mitochondrial functionality by different means. FAD-linked PSs mutations may alter the expression/sensitivity of ER Ca2+ release channels (RyR and IP3R) leading to an exaggerated ER Ca2+ release that in turn may cause abnormal mitochondrial Ca2+ uptake. wt PSs, but not the FAD mutants, were reported to form Ca2+ permeable leak channels in the ER providing a clear explanation for the enhanced Ca2+ release found in different AD models. APP can interact with the mitochondrial TIM/TOM protein import complex. The presence of an acidic domain within APP sequence may be responsible for an incomplete mitochondrial translocation that, in turn, inhibited the entry of nuclear-encoded mitochondrial proteins. Mitochondrial Aβ accumulation has been correlated with impaired enzymatic activities of cytochrome c oxidase (Cyt c-OX) and inhibition of mitochondrial Aβ-binding alcohol dehydrogenase (ABAD), leading to mitochondrial oxidative damage. Intra-mitochondrial Aβ was demonstrated to directly interact with cyclophilin D (CypD), the PTP component that binds CsA and renders the channel more sensitive to Ca2+, making AD mitochondria more sensitive to PTP opening. The origin of intra-mitochondrial Aβ peptides is however unclear. ER, endoplasmic reticulum; OMM outer mitochondrial membrane. IMS, intermembrane space; IMM, inner mitochondrial membrane.

Fig. 3

Mutant Huntingtin (mutHtt) impairs mitochondrial function by transcriprional and non-trascriptional mechanisms. The transcriptional effects are mediated by nuclear translocation of mutHtt. One important consequence of the regulation of gene transcription is the downregulation of PGC1α, and thus the reduced expression of nuclear-encoded mitochondrial proteins involved in the respiratory chains and in the oxidative-stress defense. MutHtt also associates with the outer mitochondrial membrane (OMM) directly affecting the PTP opening susceptibility and making striatal neurons more vulnerable to excitotoxic stimuli. MutHtt reduces complex II activity and the treatment with the complex II inhibitor 3-nitropropionic acid (3-NPA) induces striatal neurodegeneration in vitro and in vivo. The association of mutHtt with HAP-1A and with the IP3R type I facilitates ER Ca2+ release, thus making mitochondria more susceptible to Ca2+ overload. ER, endoplasmic reticulum; IMS, intermembrane space; IMM, inner mitochondrial membrane.

Fig. 4

Mutations in familial PD-linked genes encoding α-synuclein (α-syn), parkin, pink1, DJ-1 and LRRK2 cause mitochondrial dysfunctions through common intersecting pathways. Mutant α-syn promotes Ca2+ influx and mitochondrial Ca2+ overload and mutant parkin exacerbates this effect. DJ-1, PINK1 and Parkin may act in series on the same protein targets: genetic data suggest that pink1 is upstream of parkin, and that all of them exert a protective role preserving mitochondrial functions, morphology and preventing mitochondrial-induced apoptosis. LRRK2 mutations induce apoptotic death through cytochrome c release and activation of caspase-3. Complex I activity is reduced in PD and its inhibition by MPTP or rotenone causes dopaminergic degeneration. Mutations in mtDNA-encoded complex I subunits also cause PD. PM, plasma membrane; OMM outer mitochondrial membrane; IMS, intermembrane space; IMM, inner mitochondrial membrane.