Mitochondrial calcium cycling in neuronal function and neurodegeneration.

Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca) buffering, and apoptotic signaling. In neurons, Ca buffering is particularly important as it helps to shape Ca signals and to regulate numerous Ca-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca uniporter (MCU) and other molecular components of mitochondrial Ca transport has provided insight into the roles that mitochondrial Ca regulation plays in neuronal function in health and disease. In this review, we discuss the many roles of mitochondrial Ca uptake and release mechanisms in normal neuronal function and highlight new insights into the Ca-dependent mechanisms that drive mitochondrial dysfunction in neurologic diseases including epilepsy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also consider how targeting Ca uptake and release mechanisms could facilitate the development of novel therapeutic strategies for neurological diseases.