RESUMEN
Radiation-induced heart damage caused by low-dose X-rays has a significant impact on tumour patients' prognosis, with cardiac hypertrophy being the most severe noncarcinogenic adverse effect. Our previous study demonstrated that mitophagy activation promoted cardiac hypertrophy, but the underlying mechanisms remained unclear. In the present study, PARL-IN-1 enhanced excessive hypertrophy of cardiomyocytes and exacerbated mitochondrial damage. Isobaric tags for relative and absolute quantification-based quantitative proteomics identified NDP52 as a crucial target mediating cardiac hypertrophy induced by low-dose X-rays. SUMOylation proteomics revealed that the SUMO E3 ligase MUL1 facilitated NDP52 SUMOylation through SUMO2. Co-IP coupled with LC-MS/MS identified a critical lysine residue at position 262 of NDP52 as the key site for SUMO2-mediated SUMOylation of NDP52. The point mutation plasmid NDP52K262R inhibited mitophagy under MUL1 overexpression, as evidenced by inhibition of LC3 interaction with NDP52, PINK1 and LAMP2A. A mitochondrial dissociation study revealed that NDP52K262R inhibited PINK1 targeting to endosomes early endosomal marker (EEA1), late/lysosome endosomal marker (LAMP2A) and recycling endosomal marker (RAB11), and laser confocal microscopy confirmed that NDP52K262R impaired the recruitment of mitochondria to the autophagic pathway through EEA1/RAB11 and ATG3, ATG5, ATG16L1 and STX17, but did not affect mitochondrial delivery to lysosomes via LAMP2A for degradation. In conclusion, our findings suggest that MUL1-mediated SUMOylation of NDP52 plays a crucial role in regulating mitophagy in the context of low-dose X-ray-induced cardiac hypertrophy. Two hundred sixty-second lysine of NDP52 is identified as a key SUMOylation site for low-dose X-ray promoting mitophagy activation and cardiac hypertrophy. Collectively, this study provides novel implications for the development of therapeutic strategies aimed at preventing the progression of cardiac hypertrophy induced by low-dose X-rays.
Asunto(s)
Mitofagia , Proteínas Nucleares , Proteínas Quinasas , Humanos , Cardiomegalia/genética , Cromatografía Liquida , Lisina/metabolismo , Mitofagia/genética , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Sumoilación , Espectrometría de Masas en Tándem , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Rayos X , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismoRESUMEN
The quality of life of patients with certain diseases may be improved through the development of technologies and advancements in pharmacology, with the aim of prolonging their life. However, congestive heart failure (CHF), as well their complications, continue to be the leading cause of disease-associated death. The mechanisms underlying the development and progression of diabetes and CHF have been uncovered in a stepwise manner and the understanding of these mechanisms has improved the management of these diseases, resulting in reduced mortality and morbidity rates; however, CHF remains the leading cause of death worldwide, particularly in developed countries. In the past decades, research has indicated that several supplements and naturally occurring compounds may be used to treat muscle weakness, for cardiac failure management, rehabilitation following myocardial ischemia-reperfusion and various complications of diabetes. D-ribose is an essential component of the respiratory, skeletal and nervous systems and is a popular compound, as its supplementation may have beneficial effects. In the present review, the physiological roles, toxic reactions and the potential use of D-ribose in the management of clinical diseases are summarized.
