The article "Mitophagy-related regulated cell death: molecular mechanisms and disease implications" by Molin Yang, Xiang Wei, Xin Yi, and Ding-Sheng Jiang reviews the role of mitophagy in various forms of regulated cell death (RCD) and its implications in diseases. Mitophagy, the selective clearance of mitochondria through autophagy, is crucial for maintaining mitochondrial quality control and homeostasis. The review highlights that mitophagy is involved in different forms of RCD, including autophagic cell death (ACD), apoptosis, pyroptosis, necroptosis, ferroptosis, parthanatos, entotic cell death, and NETotic cell death. Key points include: 1. **Molecular Mechanisms**: Mitophagy is regulated by both ubiquitin-dependent and ubiquitin-independent pathways. The PINK1-Parkin pathway is a primary mechanism for mitophagy induction, involving the stabilization of PINK1 on the outer mitochondrial membrane (OMM) and subsequent phosphorylation of Parkin, which recruits mitophagy receptors to initiate mitophagy. 2. **Regulatory Roles in RCD**: - **Autophagic Cell Death (ACD)**: Excessive mitophagy can induce ACD, leading to the formation of autophagosomes and autolysosomes. This process is regulated by the ULK1 complex, PI3K-III complex, and ubiquitin-like conjugation systems. - **Apoptosis**: Mitophagy can inhibit or promote apoptosis, depending on the context. Inhibitors of apoptosis like BCL2 are upregulated, while pro-apoptotic proteins are downregulated. However, excessive mitophagy can also promote apoptosis by degrading functional mitochondria. - **Pyroptosis**: Mitophagy inhibits pyroptosis by reducing mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA), which are key mediators of NLRP3 inflammasome activation. However, excessive mitophagy can also promote pyroptosis in certain contexts. - **Necroptosis**: Mitophagy can inhibit necroptosis by reducing mtROS and mtDNA, but it can also promote necroptosis under certain conditions. - **Ferroptosis**: Mitophagy can induce ferroptosis by increasing cellular ROS levels and degrading antioxidant enzymes like GPX4. 3. **Disease Implications**: - **Degenerative Diseases**: Mitophagy-related RCD is involved in the pathogenesis of Alzheimer's disease, Parkinson's disease, and osteoarthritis. - **Tumors**: Targeting mitophagy to induce RCD in tumor cells can help overcome chemotherapy resistance. - **Drug and Poison Damage**: Mitophagy-related RCD is a potential mechanism of drug toxicity, and targeting mitophagy can reduce drug-induced damage.The article "Mitophagy-related regulated cell death: molecular mechanisms and disease implications" by Molin Yang, Xiang Wei, Xin Yi, and Ding-Sheng Jiang reviews the role of mitophagy in various forms of regulated cell death (RCD) and its implications in diseases. Mitophagy, the selective clearance of mitochondria through autophagy, is crucial for maintaining mitochondrial quality control and homeostasis. The review highlights that mitophagy is involved in different forms of RCD, including autophagic cell death (ACD), apoptosis, pyroptosis, necroptosis, ferroptosis, parthanatos, entotic cell death, and NETotic cell death. Key points include: 1. **Molecular Mechanisms**: Mitophagy is regulated by both ubiquitin-dependent and ubiquitin-independent pathways. The PINK1-Parkin pathway is a primary mechanism for mitophagy induction, involving the stabilization of PINK1 on the outer mitochondrial membrane (OMM) and subsequent phosphorylation of Parkin, which recruits mitophagy receptors to initiate mitophagy. 2. **Regulatory Roles in RCD**: - **Autophagic Cell Death (ACD)**: Excessive mitophagy can induce ACD, leading to the formation of autophagosomes and autolysosomes. This process is regulated by the ULK1 complex, PI3K-III complex, and ubiquitin-like conjugation systems. - **Apoptosis**: Mitophagy can inhibit or promote apoptosis, depending on the context. Inhibitors of apoptosis like BCL2 are upregulated, while pro-apoptotic proteins are downregulated. However, excessive mitophagy can also promote apoptosis by degrading functional mitochondria. - **Pyroptosis**: Mitophagy inhibits pyroptosis by reducing mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA), which are key mediators of NLRP3 inflammasome activation. However, excessive mitophagy can also promote pyroptosis in certain contexts. - **Necroptosis**: Mitophagy can inhibit necroptosis by reducing mtROS and mtDNA, but it can also promote necroptosis under certain conditions. - **Ferroptosis**: Mitophagy can induce ferroptosis by increasing cellular ROS levels and degrading antioxidant enzymes like GPX4. 3. **Disease Implications**: - **Degenerative Diseases**: Mitophagy-related RCD is involved in the pathogenesis of Alzheimer's disease, Parkinson's disease, and osteoarthritis. - **Tumors**: Targeting mitophagy to induce RCD in tumor cells can help overcome chemotherapy resistance. - **Drug and Poison Damage**: Mitophagy-related RCD is a potential mechanism of drug toxicity, and targeting mitophagy can reduce drug-induced damage.