Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart

Abstract

Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca²⁺) handling, mitochondrial Ca²⁺ overload, and oxidative stress. In cardiomyocytes, Ca²⁺ not only regulates excitation-contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, thereby controlling the function and actual destiny of the cell. Understanding the mechanisms of mitochondrial Ca²⁺ uptake and the molecular pathways involved in the regulation of increased mitochondrial Ca²⁺ influx is an ongoing challenge in order to identify novel therapeutic targets to alleviate the burden of heart failure. In this review, we discuss the mechanisms underlying altered mitochondrial Ca²⁺ handling in heart failure and the potential therapeutic strategies.

Keywords: calcium; heart failure; mitochondria.

Figure 2

Cysteine residues of ryanodine receptors prone to oxidation by ROS. (A) Evolutionary conservation of the hyper-active cysteines (red) across the RyR isoforms 1 and 2 in a rabbit, pig, mouse, and human. (B) Schematic diagram of the domain architecture of RyR2. Red circle in the diagram indicates the cysteines prone to oxidation for each RyR2 domain according to [243]. The same applies for the yellow circles, but according to [253] (C) Human RyR2 structure (PDB: 7UA3) showing the top and side views (left). The discussed oxidized cysteines are indicated in the close-up views (right). * means conserved residue among species.

Figure 1

Physical interaction and Ca²⁺ transfer from the SR to the mitochondria in cardiomyocytes: during the depolarization phase of the cardiac action potential, Ca²⁺ enters the cardiomyocyte through voltage-activated L-type Ca²⁺ channels (CaV1.2) and triggers RyR2 to open and release Ca²⁺ from SR Ca²⁺ stores through calcium-induced calcium release (CICR). RyR2 activity can be increased by CaMKII or PKA phosphorylation, in response to stress. Ca²⁺ release from the SR by RyR2 creates high [Ca²⁺]_cyt microdomains for mitochondrial Ca²⁺ uptake. Close contact points between the SR and mitochondria are controlled by SR mitofusin 2 (MFN2) tethering to MFN2 and MFN1 on the outer mitochondrial membrane (OMM), further creating microdomains of a high Ca²⁺ concentration in the vicinity of mitochondria. Ca²⁺ release from the SR by IP3R transits through the protein complex formed by IP3R/GRP75/VDAC and enters the mitochondria through the MCU, later being removed by mNCLX. Ca²⁺ activates complex III of the electron transport chain, ATP Synthase, several dehydrogenases in the TCA cycle, mPTP, CaMKII, and contraction of the sarcomeres. To induce repolarization, SERCA2a and NCX cycle Ca²⁺ out of the cytosol.