Intracellular calcium signaling pathways during liver ischemia and reperfusion.
Calcium plays a major role in intracellular signaling mechanisms during ischemia reperfusion (I/R) injury of a liver cell. Under ischemic conditions, the absence of oxygen arrests oxidative phosphorylation, thereby eliminating the energy source by which hepatocellular mechanisms maintain homeostasis of calcium. This, in turn, leaves nonselective plasma membrane influx pores unopposed and results in a net increase in intracellular calcium concentrations. Subsequent reperfusion marks the onset and progression of apoptosis and necrosis, as it involves inflammatory responses as well as free-radical formation due to re-oxygenation of cells. These processes destroy the structural integrity of organelles, leading to disruptive redistribution of calcium between cellular and subcellular compartments. This initial elevation and later imbalance of intracellular calcium concentrations associated with I/R induce various molecular responses within each organelle. In the cytoplasm, a series of pro-apoptotic pathways involving various calcium sensitive enzymes are activated. The injury is further exacerbated in the endoplasmic reticulum (ER) due to the malfunction of mechanisms responsible for intracellular calcium sequestration. Both the mitochondria and the nucleus are also adversely affected, as their structural integrity and physiologic functions are disrupted. To date, however, the precise pathophysiology of these calcium-mediated signaling pathways is not fully understood due to its complex nature. This review aims to systematically examine the current literature about individual molecular signaling pathways in the cytoplasm, ER, mitochondria, and the nucleus prior to causing time-sensitive progression of permanent tissue injury.
Chang
Wilson J
WJ
Kalamazoo Center for Medical Studies, Michigan State University, Kalamazoo, Michigan, USA.
Chehab
Monzer
M
Kink
Shaun
S
Toledo-Pereyra
Luis H
LH
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D003593:Cytoplasm / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology; D006801:Humans; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008928:Mitochondria / Q000502:physiology; D015427:Reperfusion Injury / Q000503:physiopathology*