Mitochondrial calcium cycling in neuronal function and neurodegeneration

Abstract

Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca2+) buffering, and apoptotic signaling. In neurons, Ca2+ buffering is particularly important as it helps to shape Ca2+ signals and to regulate numerous Ca2+-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca2+ uniporter (MCU) and other molecular components of mitochondrial Ca2+ transport has provided insight into the roles that mitochondrial Ca2+ regulation plays in neuronal function in health and disease. In this review, we discuss the many roles of mitochondrial Ca2+ uptake and release mechanisms in normal neuronal function and highlight new insights into the Ca2+-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 Ca2+ uptake and release mechanisms could facilitate the development of novel therapeutic strategies for neurological diseases.

Mitochondrial and cellular function in fibroblasts and reprogrammed neural cells: insights into major depression as a mitochondria-associated disease

“…Here, the mitochondrial Ca 2+ levels in the analyzed cell lineages do only partially follow the observed MMP or cytosolic Ca 2+ levels. However, these parameters are also affected by secondary mechanisms such as plasmalemmal and ER Ca 2+ transporters or the activity of the uncoupling proteins and the ATP-synthase of the inner mitochondrial membrane (IMM) 46 .…”

“…but also generates oxygen stress and leads to damage of DNA, lipids, and proteins. Moreover, various signaling pathways including Ca 2+ and steroid hormone precursors are affected 46,[48][49][50] . Among the numerous hypotheses on the etiology of psychiatric and neurological disorders, the role of mitochondria in the pathology of mental illness is attracting increasing interest.…”

Transient Receptor Potential Channels in the Healthy and Diseased Blood–Brain Barrier

“…Normally, the free intracellular concentration of Ca 2+ is very low, but when the cells are in an activated stage, its intracellular concentration is increased. 129 Upregulation of intracellular Ca 2+ levels and high pH intracellular levels are associated with several NDs and age-related disorders 76,80,130 ; based on these findings, we present a scheme in which Duitama et al 76 indicated how the alterations in Ca 2+ homeostasis induce the modifications of various cellular processes 80 (Fig. 16).…”

“…Normally, the free intracellular concentration of Ca 2+ is very low, but when the cells are in an activated stage, its intracellular concentration is increased. 129…”

Effects of lithium isotopes on sodium/lithium co-transport and calcium efflux through the sodium/calcium/lithium exchanger in mitochondria

“…Mitochondrial Ca 2+ flux was monitored using the low-affinity fluorescent label Calcium Green 5N, as a Ca 2+ indicator (Kd~14 µM) (A) Schematics of mitochondrion with MCU and NCLX channels. MCU passes Ca 2+ inside the mitochondrion (Ca 2+ influx); NCLX passes Na + or Li + inside the mitochondrion in exchange for Ca 2+ transport outside (Ca 2+ efflux) (Rossi, Pizzo, and Filadi, 2019;Walters and Usachev, 2023). (B) Ca 2+ -induced fluorescence as a measure of Ca 2+ influx through MCU and Ca 2+ efflux through NCLX in exchange for Na + .…”