Calcium and Cell Death: The Mitochondrial Connection

Part of the Subcellular Biochemistry book series (SCBI, volume 45)


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


Ca2+ channel mitochondria permeability transition pore apoptosis 


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© Springer 2007

Authors and Affiliations

    • 1
    • 1
  1. 1.Department of Biomedical SciencesUniversity of PadovaViale Giuseppe Colombo 3Italy

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