Mitochondrial dynamics, mitophagy and cardiovascular disease

Abstract

Cardiac hypertrophy is often initiated as an adaptive response to haemodynamic stress or myocardial injury, and allows the heart to meet an increased demand for oxygen. Although initially beneficial, hypertrophy can ultimately contribute to the progression of cardiac disease, leading to an increase in interstitial fibrosis and a decrease in ventricular function. Metabolic changes have emerged as key mechanisms involved in the development and progression of pathological remodelling. As the myocardium is a highly oxidative tissue, mitochondria play a central role in maintaining optimal performance of the heart. 'Mitochondrial dynamics', the processes of mitochondrial fusion, fission, biogenesis and mitophagy that determine mitochondrial morphology, quality and abundance have recently been implicated in cardiovascular disease. Studies link mitochondrial dynamics to the balance between energy demand and nutrient supply, suggesting that changes in mitochondrial morphology may act as a mechanism for bioenergetic adaptation during cardiac pathological remodelling. Another critical function of mitochondrial dynamics is the removal of damaged and dysfunctional mitochondria through mitophagy, which is dependent on the fission/fusion cycle. In this article, we discuss the latest findings regarding the impact of mitochondrial dynamics and mitophagy on the development and progression of cardiovascular pathologies, including diabetic cardiomyopathy, atherosclerosis, damage from ischaemia-reperfusion, cardiac hypertrophy and decompensated heart failure. We will address the ability of mitochondrial fusion and fission to impact all cell types within the myocardium, including cardiac myocytes, cardiac fibroblasts and vascular smooth muscle cells. Finally, we will discuss how these findings can be applied to improve the treatment and prevention of cardiovascular diseases.

Figure 1. Complex interplay between mitochondrial fusion and fission supports cell homeostasis

Mitochondrial dynamics sustains a balance between the processes of mitochondrial fusion and fission to maintain the proper function of this complex organelle. Mitochondrial fusion is regulated by mitofusin (MFN) 1 and 2 and optical atrophy protein 1 (OPA1). This allows for exchange of material (matrix components, damaged mitochondrial DNA), as well as promoting a balance in bioenergetic properties (e.g. mitochondrial membrane potential). On the other hand, DRP1 and its adapter proteins FIS1, MFF and MiD49/51 control mitochondrial fission. This process is necessary for various processes throughout the life of the cell, such as redistribution of mitochondria in mitosis, as well as release of cytochrome c during cell death by apoptosis. Moreover, mitochondrial fission is required for selective mitochondrial degradation (mitophagy).

Figure 2. Mitochondrial dynamics and cardiovascular diseases

Summary of important molecular events in cardiovascular diseases associated with mitochondrial fission (red zone) and therapeutic interventions or molecular processes related to mitochondrial fusion and linked with an improved cardiovascular function (green zone).

Figure 3. Mitophagy

The process of selective targeting of mitochondria by autophagy (mitophagy) is coordinated with mitochondrial fusion and fission to ensure proper mitochondrial quality control. Mitochondrial fission isolates damaged mitochondria (usually with low membrane potential) to initiate the process of mitophagy. Under conditions of low mitochondrial membrane potential, PINK1 kinase accumulates on a mitochondrion and phosphorylates MFN2 (A). Parkin E3 ligase binds phosphorylated MFN2 and localizes to the mitochondrion (B). To catalyse the ubiquitination of several proteins on the mitochondrial surface, various adapter proteins, such as BNIP3 and NIX, are associated with the autophagy machinery (C), ultimately facilitating elimination of mitochondrial content (D).

Figure 4. Mitochondrial dynamics and cardiovascular remodelling

Alterations in mitochondrial dynamics have a significant role in cardiovascular remodelling. Cardiac hypertrophy, diabetic cardiomyopathy, myocardial infarction and atherosclerosis share common pathological mechanisms and features related to fragmentation of the mitochondrial network. Mitochondrial morphological alterations finally lead to metabolic dysfunction, damage of mitochondrial components (mtDNA) and/or cell death.