Calcium and cell death: the mitochondrial connection.
Physiological stimuli causing an increase of cytosolic free Ca2+ [Ca2+], 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 microM range, which allows the activation of Ca2(+)-regulated enzymes of the Krebs cycle; and it rapidly returns to the resting level if the [Ca2+], 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.
Bernardi
P
P
Department of Biomedical Sciences, University of Padova, Viale Giuseppe Colombo 3, 35121 Padova, Italy.
Rasola
A
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology; D006801:Humans; D008107:Liver Diseases / Q000503:physiopathology; D008928:Mitochondria / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000503:physiopathology; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology; D051336:Mitochondrial Membranes / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D009135:Muscular Diseases / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009422:Nervous System Diseases / Q000503:physiopathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology
D015220:Calcium Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019253:Proto-Oncogene Proteins c-bcl-2; C034703:mitochondrial calcium uniporter; D002118:Calcium