Mitochondrial calcium signaling in cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a primary liver cancer whose diagnosis and treatment remain challenging. Although recent developments derived from molecular characterization of CCAs have led to the availability of new pharmacological agents, a better understanding of the genetic and molecular alterations in CCA is still required for the development of more effective or broader targeting treatments. One emerging signaling pathway of interest in the pathogenesis of CCA is ER to mitochondrial Ca²⁺ signaling. This pathway is of particular importance because it regulates both cell death through apoptosis and necrosis, and metabolic reprograming of cancer cells through regulation of energy metabolism in mitochondria. Here we discuss the latest findings regarding the dysregulation of mitochondrial Ca²⁺ signals and its key regulatory molecules with a special focus on the intracellular Ca²⁺ channels of the inositol 1,4,5-trisphosphate receptor (ITPR) family. We also discuss the role of ER-mitochondrial contact sites in determining mitochondrial health and how these points of contact between organelles might represent a druggable target in CCA.

Keywords

Cholangiocarcinoma / cholangiocytes / mitochondria / inositol 1,4,5-trisphosphate-receptors / calcium signaling / membrane contact sites / mitochondria-associated endoplasmic reticulum membranes / apoptosis / cell proliferation / energy metabolism

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