Brain calcium homeostasis and mitochondrial function

Abstract

The high efficiency of the neuronal calcium signaling depends on the calcium distribution in intracellular stores such as ER, Golgi apparatus and mitochondria, in association with changes in ionic gradients across their membranes. Although restoring ionic gradients is energetically costly, a rise in intracellular Ca2+ acts through multiple pathways to increase ATP synthesis, matching energy supply to demand. Synaptic transmission leads to the release of neurotransmitters, the process of learning and the formation and consolidation of memory. In addition, through the regulation of specific gene pools, the long-term potentiation (LTP) or depression of synaptic transmission are all specific neuronal processes that are under the control of Ca2+ signals. Increased Ca2+ influx through the mitochondria is mediated by calcium uniporter (MCU); although the physiological importance of the MCU complex during respiration of CNS neurons is not yet fully clarified, abnormal mitochondrial Ca2+ signalling causes pathology, indicating that, the fine tuning of Ca2+ signals plays a key role in shaping mitochondrial bioenergetics. Not only dehydrogenase activity is closely related with the calcium entry to the mitochondria, but many other pathways such as the reactive oxygen species (ROS) production are the consequence of an important calcium-crosstalk. The mitochondrial production of superoxide anion as a by-product of oxidative metabolism is a major source of intracellular ROS production. It has been suggested that the increased metabolic rate would consume more oxygen resulting in increased respiratory chain electron leakage and ROS levels. If cells become somehow unable to control the free concentration of Ca2+, letting it increase persistently in their interior above the optimal 100?200 nM level, all Ca2+ controlled activities would become permanently activated, including those (e.g., proteases) that are potentially harmful to cells. Therefore, various degrees of damage, up to cell death would inevitably ensue. Cells may activate rescue attempts in order to survive until the emergency disappears. The impaired ability of neurons to maintain an adequate energy level may impact Ca2+ signaling in aging and in different neurodegenerative disease processes.