Mitochondrial calcium handling and neurodegeneration: when a good signal goes wrong

Mitochondria represent the main powerhouse of the cell, producing the majority of ATP molecules needed for all the cell processes. In particular, excitable cells, such as neurons, with their high-energy demanding activities, deeply rely on mitochondrial oxidative phosphorylation (OXPHOS) for their bioenergetics. Moreover, the rate of ATP synthesis is dynamically matched with synaptic activity by mean of calcium (Ca)-signals, modulating different mitochondrial enzymes and transporters. Finally, several neuronal activities, from the modulation of the overall cytosolic Ca signal to the production of reactive oxygen species (ROS) and cell death, are tuned by mitochondrial Ca handling. Multiple alterations in this specific signaling pathway are common in different neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), highlighting its importance for neurons.