{"id":372,"title":"Early mitophagy defects and impaired mitochondrial energy metabolism drive target organ damage progression: Lessons from the Fabry heart","title_zh":"早期线粒体自噬缺陷与线粒体能量代谢受损驱动靶器官损伤进展：来自Fabry心脏的启示","url":"https://pubmed.ncbi.nlm.nih.gov/42945215","doi":"10.1016/j.celrep.2026.118183","pmid":"42945215","journal":"Cell Rep","kind":"paper","lang":"en","published_at":"2026-10-26T00:00:00+00:00","fetched_at":"2026-11-08T03:44:12+00:00","authors":["Gambardella J","Fiordelisi A","Cerasuolo FA","Buonaiuto A","Avvisato R","Viti A","Sommella E","Campiglia P","D'Argenio V","Prevete N","Pezone A","D'Apice S","Altobelli GG","Varzideh F","Pande S","Paolillo R","Perrino C","Riccio E","Pisani A","Bianco A","Sadoshima J","Spinelli L","Santulli G","Sorriento D","Iaccarino G"],"primary_topic":"repro-aging","topics":[{"slug":"repro-aging","score":6.0,"hits":["mitochondria","mitochondrial","mitochondrial dysfunction"]},{"slug":"ivg-stem","score":1.0,"hits":["pgc"]}],"topic_score":6.0,"preference_score":0.0,"preference_labels":[],"llm_score":38.0,"final_score":46.0,"score_dims":{"novelty":78,"rigor":75,"impact":35,"relevance":10,"translation":20},"recommend_reason":"研究本身机制扎实，但主题为Fabry病心肌病，不属于生殖医学/辅助生殖核心范畴；仅对关注线粒体-溶酶体轴与生殖衰老交叉机制者有一定间接参考价值，不宜作为生殖每日必读。","keywords":["Fabry病","线粒体自噬","线粒体能量代谢","溶酶体功能障碍","心肌病","L-精氨酸"],"selected":0,"story_id":null,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-top-journals","source_name":"PubMed · CNS/大子刊/四大医学刊（生殖相关）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"cell-rep","journal_tier":"cns-sub","journal_if":7.5,"is_mock":false,"summary_zh":"该研究以Fabry病（GLA缺乏致Gb3蓄积）心肌病为模型，结合人源化FD小鼠、胚胎成纤维细胞及新生/成体心肌细胞，发现早期线粒体自噬受损、线粒体呼吸下降和ROS升高，并与溶酶体功能障碍形成恶性循环；随年龄进展导致功能异常线粒体堆积、能量衰竭、凋亡、心肌肥厚和舒张功能障碍。L-精氨酸可通过NO/PGC-1α依赖途径挽救线粒体并预防心脏异常，提示溶酶体-线粒体轴是可干预靶点。","summary":"Increasing evidence supports a pathogenic role for impaired energy metabolism in organ damage. Genetic diseases provide opportunities to investigate these mechanisms, as exemplified by Fabry disease (FD), caused by an α-galactosidase A (GLA) deficiency and globotriaosylceramide (Gb3) accumulation, with cardiomyopathy as the leading cause of death. Beyond Gb3 storage, impaired energy metabolism may contribute to cardiomyopathy. Here, we demonstrate mitochondrial dysfunction in FD heart and its therapeutic targeting. Using a humanized FD mouse model (R301Q-Tg/GLA knockout), embryonic fibroblasts, and neonatal and adult cardiomyocytes, we found impaired mitophagy and mitochondrial respiration, increased reactive oxygen species, and a vicious cycle aggravating lysosomal dysfunction. These defects progressed with age, causing accumulation of dysfunctional mitochondria, energetic failure, apoptosis, cardiac hypertrophy, and diastolic dysfunction. L-arginine, promoting NO/PGC-1α-dependent mitochondrial rescue, prevented cardiac abnormalities. Our findings identify mitochondrial dysfunction as a key driver of FD cardiomyopathy and reveal the lysosome-mitochondria axis as a targetable pathway in FD and beyond.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}