Interaction of Mitochondrial Calcium and ROS in Neurodegeneration

Abstract

Neurodegenerative disorders are currently incurable devastating diseases which are characterized by the slow and progressive loss of neurons in specific brain regions. Progress in the investigation of the mechanisms of these disorders helped to identify a number of genes associated with familial forms of these diseases and a number of toxins and risk factors which trigger sporadic and toxic forms of these diseases. Recently, some similarities in the mechanisms of neurodegenerative diseases were identified, including the involvement of mitochondria, oxidative stress, and the abnormality of Ca2+ signaling in neurons and astrocytes. Thus, mitochondria produce reactive oxygen species during metabolism which play a further role in redox signaling, but this may also act as an additional trigger for abnormal mitochondrial calcium handling, resulting in mitochondrial calcium overload. Combinations of these factors can be the trigger of neuronal cell death in some pathologies. Here, we review the latest literature on the crosstalk of reactive oxygen species and Ca2+ in brain mitochondria in physiology and beyond, considering how changes in mitochondrial metabolism or redox signaling can convert this interaction into a pathological event.

SOD1 in ALS: Taking Stock in Pathogenic Mechanisms and the Role of Glial and Muscle Cells

“…Such perturbations have been well-documented in the hSOD1(G93A) Tg mouse, in which the Ca 2+ overload in the cytoplasm [143][144][145]148], the impairment of mitochondrial Ca 2+ capacity [152][153][154], and alterations of the mitochondrial Ca 2+ extrusion system [154,155] have been reported. In addition, an increased intracellular Ca 2+ level was also reported in the spinal cord and skeletal muscle of sALS/fALS patients [156][157][158], in other ALS-related Tg mouse models [159], and in MNs derived from iPSC cell lines of fALS patients [160,161].…”

“…Indeed, it is well established that Ca 2+ and ROS are linked by a mutual interplay useful to strictly regulate cellular signaling networks. Interestingly, such connection links Ca 2+ and ROS metabolism with each other [153]. For example, Ca 2+ modulates several systems/enzymes involved in ROS production, in such a way that elevated intracellular Ca 2+ levels activate ROS-generating enzymes and free radical formation.…”

“…Following the notion that a synergy between mitochondrial Ca 2+ alterations and ROS production may play a relevant role in ALS [153,184,185], as well as the reported Ca 2+related proteome modifications in SOD1(G93A) cells, we firstly checked the expression of mitochondrial and sarcoplasmic reticulum (SR) Ca 2+ transporters in primary SMs from hSOD1(G93A) Tg mice compared to the hSOD1(WT) counterpart as control.…”

“…Increasing evidence suggests that an alteration of this finely tuned cross-talk may be responsible for many disorders, including ALS among other neurodegenerative diseases [153,192]. In particular, many studies, accomplished in different ALS models (mutant SOD1, TDP-43, or FUS/TLS), demonstrated that an impairment of the ER-mitochondria communication [188,193,194] causes an altered mitochondrial Ca 2+ capacity, inducing a significant decrease in the mitochondrial membrane potential and an increase in the rate of the production of mitochondrial ROS [153].…”

“…Increasing evidence suggests that an alteration of this finely tuned cross-talk may be responsible for many disorders, including ALS among other neurodegenerative diseases [153,192]. In particular, many studies, accomplished in different ALS models (mutant SOD1, TDP-43, or FUS/TLS), demonstrated that an impairment of the ER-mitochondria communication [188,193,194] causes an altered mitochondrial Ca 2+ capacity, inducing a significant decrease in the mitochondrial membrane potential and an increase in the rate of the production of mitochondrial ROS [153]. However, further findings are needed to finally determine if the dysfunctional Ca 2+ fluxes observed in ALS-related primary SMs-that we may argue be related to an altered expression of Ca 2+ transporters-lead to an unbalanced redox signaling and impaired SM functionality.…”