Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia - reperfusion injury

Abstract

Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion (I/R) injury. Mitochondrial quality control (MQC) mechanisms, a series of adaptive responses that preserve mitochondrial structure and function, ensure cardiomyocyte survival and cardiac function after I/R injury. MQC includes mitochondrial fission, mitochondrial fusion, mitophagy and mitochondria-dependent cell death. The interplay among these responses is linked to pathological changes such as redox imbalance, calcium overload, energy metabolism disorder, signal transduction arrest, the mitochondrial unfolded protein response and endoplasmic reticulum stress. Excessive mitochondrial fission is an early marker of mitochondrial damage and cardiomyocyte death. Reduced mitochondrial fusion has been observed in stressed cardiomyocytes and correlates with mitochondrial dysfunction and cardiac depression. Mitophagy allows autophagosomes to selectively degrade poorly structured mitochondria, thus maintaining mitochondrial network fitness. Nevertheless, abnormal mitophagy is maladaptive and has been linked to cell death. Although mitochondria serve as the fuel source of the heart by continuously producing adenosine triphosphate, they also stimulate cardiomyocyte death by inducing apoptosis or necroptosis in the reperfused myocardium. Therefore, defects in MQC may determine the fate of cardiomyocytes. In this review, we summarize the regulatory mechanisms and pathological effects of MQC in myocardial I/R injury, highlighting potential targets for the clinical management of reperfusion.

Keywords: Apoptosis; Cardiomyocyte I/R injury; Fusion; Mitochondrial death; Mitochondrial fission; Mitochondrial quality control; Mitophagy; Necroptosis.

Graphical abstract

Figure 1

Overview of mitochondrial quality control (MQC) under physiological conditions and I/R injury. MQC coordinates various processes (fission, fusion, mitophagy and mitochondria-controlled cell death) to ensure cellular homeostasis. Mitochondrial dysfunction, amplified by failing quality-control processes, is believed to be a major mechanism of cardiac I/R injury. Several potential targets of MQC could be harnessed to treat cardiac I/R injury by inhibiting mitochondrial fission, promoting mitochondrial fusion, moderately activating mitophagy and inhibiting mitochondria-dependent cell death.

Figure 2

Mitochondrial fission is regulated by dynamin-related protein 1 (DRP1) and its receptors, including mitochondrial fission factor (MFF), mitochondrial fission one protein (FIS1). Increased mitochondrial fission is associated with oxidative stress, mitochondrial DNA (mtDNA) damage, mitochondrial membrane potential reduction and mitochondrial apoptosis activation.

Figure 3

Mitochondrial fusion is controlled by outer mitochondrial membrane (OMM)-localized mitofusin 2 (MFN2) and inner mitochondrial membrane (IMM)-localized optic atrophy 1 (OPA1). Increased mitochondrial fusion inhibits mitochondrial fission, sustains mitochondrial potential, promotes mitochondrial bioenergetics and suppresses mitochondrial apoptosis.

Figure 4

The most recognized mitophagy pathway in mammalian cells is mediated by PARKIN, a receptor-independent pathway. In addition to PARKIN-mediated mitophagy, receptor-dependent pathway for mitophagy induction includes Fun14 domain-containing protein 1 (FUNDC1). Mechanismically, the targeted mitochondria are engulfed by the pre-autophagosome, forming an autophagosome. Subsequently, microtubule-associated protein 1A/1B-light chain 3 (LC3) binds to phosphatidylethanolamine, generating the LC3-phosphatidylethanolamine conjugate (LC3II). Finally, the lysosome induces the proteolytic degradation of the autophagosomal proteins, nucleic acids, carbohydrates and lipids, which are recycled by the cell to restore homeostasis.

Figure 5

Mitochondrial death includes apoptosis and necroptosis. Apoptosis is regulated by outer mitochondrial membrane (OMM) permeabilization, mitochondrial membrane potential reduction, caspase-9 activation. Necroptosis is induced by the activation of RIPK3/MLKL pathway and the mPTP opening. Then, mitochondrial electron transport chain dysfunction and tricarboxylic acid cycle termination contribute to ATP exhaustion, cytoplasmic swelling, and membrane rupture.

Figure 6

Involvement of mitochondrial quality control in cardiac I/R injury. Under physiological conditions, healthy mitochondria support the functions of cardiomyocytes by ensuring optimal catabolic and anabolic metabolism and regulating the intracellular trafficking of Ca²⁺. Additionally, an intact mitochondrial network maintains inflammatory homeostasis and tissue integrity by preventing the activation of signal transduction cascades that lead to pro-inflammatory factor secretion and regulated cell death. Mitochondrial dysfunction is accompanied by metabolic derangements and alterations in the intracellular Ca²⁺ flux, and also promotes an inflammatory milieu and regulated cell death, which culminates in tissue loss.