Physiological stimuli causing an increase of cytosolic free Ca2+ [Ca2+]c or the release of Ca2+ from the endoplasmic reticulum invariably induce mitochondrial Ca2+ uptake, with a rise of mitochondrial matrix free [Ca2+] ([Ca2+]m). The [Ca2+]m rise occurs despite the low affinity of the mitochondrial Ca2+ uptake systems measured in vitro and the often limited amplitude of the cytoplasmic [Ca2+]c increases. The [Ca2+]m increase is typically in the 0.2–3 μM range, which allows the activation of Ca2+-regulated enzymes of the Krebs cycle; and it rapidly returns to the resting level if the [Ca2+]c rise recedes due to activation of mitochondrial efflux mechanisms and matrix Ca2+ buffering. Mitochondria thus accumulate Ca2+ and efficiently control the spatial and temporal shape of cellular Ca2+ signals, yet this situation exposes them to the hazards of Ca2+ overload. Indeed, mitochondrial Ca2+, which is so important for metabolic regulation, can become a death factor by inducing opening of the permeability transition pore (PTP), a high conductance inner membrane channel. Persistent PTP opening is followed by depolarization with Ca2+ release, cessation of oxidative phosphorylation, matrix swelling with inner membrane remodeling and eventually outer membrane rupture with release of cytochrome c and other apoptogenic proteins. Understanding the mechanisms through which the Ca2+ signal can be shifted from a physiological signal into a pathological effector is an unresolved problem of modern pathophysiology that holds great promise for disease treatment
CITATION STYLE
Bernardi, P., & Rasola, A. (2007). Calcium and cell death: The mitochondrial connection. Subcellular Biochemistry, 45, 481–506. https://doi.org/10.1007/978-1-4020-6191-2_18
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