Intracellular Calcium Signaling Pathways during Liver Ischemia and Reperfusion

Abstract

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.

Aberrant Endoplasmic Reticulum Stress in Vascular Smooth Muscle Increases Vascular Contractility and Blood Pressure in Mice Deficient of AMP-Activated Protein Kinase-α2 In Vivo

“…Under stress conditions, proteins become misfolded and accumulated within the ER to provoke the unfolded protein response. 1–4 After detecting such accumulation, the ER activates transcriptional and translational pathways leading to the increased expression of ER-resident chaperones, inhibition of protein translation, and acceleration of protein degradation. 5 However, prolonged ER stress is considered a pathogenic mechanism in human diseases, including aging, 6–11 obesity, 12–14 atherosclerosis, 15–18 and diabetes mellitus.…”

Nitrite Confers Preconditioning and Cytoprotection After Ischemia/Reperfusion Injury Through the Modulation of Mitochondrial Function

“…A further influx of calcium at reperfusion causes mitochondrial calcium overload which, in conjunction with the oxidative stress, triggers PTP opening (52). Further, ROS oxidize DNA and proteins, particularly complexes of the ETC, resulting in decreased oxidative phosphorylation, as well as critical membrane lipids (including inner membrane cardiolipin) contributing to the release of cytochrome c and the initiation of the apoptotic cascade (32,52,70).…”

Comparative study of amlodipine vs. cilnidipine for the prevention of hepatic ischemia‐reperfusion injury in rat model

“…The liver is an example of organs that is frequently exposed to I/R injury during transplantation surgery which may lead to poor graft function, graft nonfunction, or even to acute and chronic graft rejection . Several factors/pathways have been implicated in the pathogenesis of I/R injury, overall, dysregulation of Ca 2+ homeostasis plays a pivotal role .…”