Mitophagy: A Potential Target for Pressure Overload-Induced Cardiac Remodelling

Abstract

The pathological mechanisms underlying cardiac remodelling and cardiac dysfunction caused by pressure overload are poorly understood. Mitochondrial damage and functional dysfunction, including mitochondrial bioenergetic disorder, oxidative stress, and mtDNA damage, contribute to heart injury caused by pressure overload. Mitophagy, an important regulator of mitochondrial homeostasis and function, is triggered by mitochondrial damage and participates in the pathological process of cardiovascular diseases. Recent studies indicate that mitophagy plays a critical role in the pressure overload model, but evidence on the causal relationship between mitophagy abnormality and pressure overload-induced heart injury is inconclusive. This review summarises the mechanism, role, and regulation of mitophagy in the pressure overload model. It also pays special attention to active compounds that may regulate mitophagy in pressure overload, which provide clues for possible clinical applications.

Figure 1

Overview of mitophagy. Mitophagy is a selective autophagy that maintains physiological functions by selectively degradation of damaged or dysfunctional mitochondria. During mitophagy, the damaged mitochondria are labeled and surrounded by vesicles which stretch to form autophagosome. Lastly, autophagosomes fuse with lysosomes to form autophagolysosomes, where hydrolases degrade the sequestered materials and released the degraded products into cytoplasm.

Figure 2

Mitochondria-related damage and potential role of mitophagy in pressure overload model. More mitochondrial cristae disorders, decreased cristae density, and mitochondrial swelling appear after pressure overloaded. Mitochondrial respiration is impaired. Oxidative stress is an important mediator in the mechanism of pathological cardiac remodelling. Under pressure overload, a variety of mechanisms regulate the increase of ROS and RNS. Under pressure overload, ROS and a variety of upstream signals also lead to mtDNA damage, resulting in pathological cardiac remodelling. mtDNA damage and ROS activate mitophagy through a variety of mechanisms. Mitophagy inhibits the adverse effects of ROS and mtDNA.

Figure 3

Mitochondrial dynamics in pressure overload model. In the pressure overload model, MFN2 was downregulated. After TAC, Mir-17-5p and Mir-106a inhibit MFN2 and cause cardiac hypertrophy. In OPA1+/- mice, TAC results in more severe cardiac remodelling and cardiac dysfunction. Increased expression of OPA1 by upregulating YME1L or TNFR2 protects hearts from pressure overload. The decreased level phosphorylation at s616 of DRP1 accompanies a decrease in mitophagy. Knockout of DRP1 aggravates mitochondrial dysfunction, cardiac hypertrophy, and cardiac dysfunction caused by pressure overload. STAT1 promotes mitochondrial division through UCP2/P-DRP1 pathway to resist TAC-induced myocardial hypertrophy. However, the use of DRP1 inhibitor Mdivi-1 improves cardiac dysfunction and cardiac remodelling after TAC.