SERCA control of cell death and survival

Abstract

Intracellular calcium (Ca²⁺⁾ is a critical coordinator of various aspects of cellular physiology. It is increasingly apparent that changes in cellular Ca²⁺ dynamics contribute to the regulation of normal and pathological signal transduction that controls cell growth and survival. Aberrant perturbations in Ca²⁺ homeostasis have been implicated in a range of pathological conditions, such as cardiovascular diseases, diabetes, tumorigenesis and steatosis hepatitis. Intracellular Ca²⁺ concentrations are therefore tightly regulated by a number of Ca²⁺ handling enzymes, proteins, channels and transporters located in the plasma membrane and in Ca²⁺ storage organelles, which work in concert to fine tune a temporally and spatially precise Ca²⁺ signal. Chief amongst them is the sarco/endoplasmic reticulum (SR/ER) Ca²⁺ ATPase pump (SERCA) which actively re-accumulates released Ca²⁺ back into the SR/ER, therefore maintaining Ca²⁺ homeostasis. There are at least 14 different SERCA isoforms encoded by three ATP2A1-3 genes whose expressions are species- and tissue-specific. Altered SERCA expression and activity results in cellular malignancy and induction of ER stress and ER stress-associated apoptosis. The role of SERCA misregulation in the control of apoptosis in various cell types and disease setting with prospective therapeutic implications is the focus of this review. Ca²⁺ is a double edge sword for both life as well as death, and current experimental evidence supports a model in which Ca²⁺ homeostasis and SERCA activity represent a nodal point that controls cell survival. Pharmacological or genetic targeting of this axis constitutes an incredible therapeutic potential to treat different diseases sharing similar biological disorders.

Keywords: Apoptosis; Calcium; Cancer; Cardiovascular diseases; Cell death; Diabetes; ER stress; Hepatostatosis; SERCA; SERCA isoforms; SERCA therapies.

Figure 1. Basic processes of cell death

Cell death occurs through three different means: apoptosis, autophagy and necrosis

Figure 2. Overview of intracellular Ca²⁺ signaling and its implications in cell death and survival

Major organelles and players regulating Ca²⁺ influx and efflux during the process of cell death. and Bcl-2, B-cell lymphoma 2; GRP75, glucose-regulated protein 75; IP₃R, inositol1,4,5-trisphosphate (IP₃) receptor; LTCC, L-type Ca²⁺ channel; MCU, mitochondrial Ca²⁺ uniporter; mPTP, mitochondrial permeabilization transition pore; NCX, Na⁺/Ca²⁺ exchanger; NFAT, nuclear factor of activated T lymphocytes; PMCA, plasma-membrane Ca²⁺ ATPase; RyR, Ryanodine Receptor; SERCA, Sarco/Endoplasmic Reticulum Ca²⁺ ATPase; STIM1, Stromal interaction molecule 1; TPC2, two-pore channel 2; TRPC, transient receptor potential canonical; VDAC, voltage-dependent anion channel. See text for further explanations

Figure 3. Consequences of elevated diastolic Ca²⁺

Increased cytosolic/diastolic Ca²⁺ activates multiple Ca²⁺-dependent kinases and proteases and triggers a cascade of signaling pathways that regulate cell growth, survival and death. Mitochondrial Ca²⁺ overload results in apoptosis through the opening of the mPTP. Mitochondria-associated Bcl-2 plays a pro-survival role.

Figure 4. ER stress-induced toxicity and cell death

External factors such as obesity, reactive oxygen species (ROS), post-translational modifications (PTMs), cytokines and nitric oxide (NO) negatively regulate the activity and/or expression of SERCA leading to ER stress activation and cytosolic Ca²⁺ rise and initiation of apoptosis and organ damage.

Figure 5. Interaction between ER and Mitochondria

Ca²⁺ is dynamically cycled between the ER and mitochondria; Serca2 utilizes ATP generated by the mitochondria to clear up cytosolic Ca²⁺ accumulation. This cycle is disrupted under pathological conditions. The ER and mitochondria are structurally and functionally connected. Functional defects in either organelle contribute to insulin resistance and diabetes (type 2 diabetes, T2DM) through induction of β-cell death and mass decline.