Mitophagy in Doxorubicin-Induced Cardiotoxicity: Insights into Molecular Biology and Novel Therapeutic Strategies

Figures

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  Figure 1. Overview of DOX-induced cardiotoxicity in cardiomyocytes. DOX treatment initiates a complex interplay of multi-focal signaling pathways that play critical roles in cellular responses. The HMGB1/TLRs/NF-κB signaling pathway is activated, leading to enhanced inflammatory responses, while the NOX/Nrf2/HO-1/ROS pathway contributes to oxidative stress by generating reactive oxygen species. Additionally, the AMPK/P53 pathway can induce cell cycle arrest and apoptosis, and the PI3K/AKT/STAT3 pathway is involved in survival signaling. Collectively, these interconnected events result in oxidative stress, mitochondrial DNA dysfunction, increased inflammation, and several forms of cell death, including apoptosis, necrosis, and autosis, ultimately impacting tissue homeostasis and function.

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  Figure 2. Landscape of the mitophagy mechanisms. Mitochondrial autophagy involves multiple interconnected mechanisms that can be broadly categorized into ubiquitin (Ub)-dependent and ubiquitin-independent pathways. The PINK1/Parkin pathway is the most well-studied ubiquitin-dependent mechanism. In addition, a group of mitochondrial autophagy receptors, such as Nix, Bnip3, and FUND1, can directly bind to LC3 without requiring extensive ubiquitination, which characterizes the ubiquitin-independent pathway. These distinct yet complementary pathways play crucial roles in regulating mitochondrial quality control and cellular homeostasis.