Frontiers in oncology · 2026
Regulatory mechanisms of mitochondrial function by cancer-derived exosomes in cachexia.
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Tomida Ryotaro, Ozaki Keisuke, Tanaka Yukako, Komatsu Rina, Hirata Syuya, Uchida Takayuki, Furukawa Junya, Nikawa Takeshi, Fukawa Tomoya
Аннотация
BACKGROUND: Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting and impaired response to conventional nutritional support, affecting up to 80% of advanced cancer patients and contributing to poor prognosis. Excessive fatty acid oxidation and mitochondrial reactive oxygen species (ROS) generation have been implicated in cachexia-associated muscle atrophy, but the underlying mechanisms remain unclear.
METHODS AND RESULTS: We investigated the role of cancer cell-derived exosomes in metabolic alterations of skeletal muscle cells. Exosomes from a pro-cachectic renal carcinoma cell line (RXF393) induced myotube atrophy, enhanced mitochondrial ROS production, impaired mitochondrial respiration, and reduced expression of isocitrate dehydrogenase 2 (IDH2) and respiratory chain complex subunits compared to observations in non-cachectic controls. miRNA profiling identified enrichment of miR-1260b in pro-cachectic exosomes, and transfection with a miR-1260b mimic reproduced these phenotypes, including IDH2 downregulation, impaired antioxidant defense, and mitochondrial dysfunction.
CONCLUSION: These findings demonstrate that cancer-derived exosomal miR-1260b suppresses IDH2, disrupts mitochondrial redox balance, and promotes muscle wasting. This study reveals a mechanistic link between exosomal miRNAs and mitochondrial dysfunction in cancer cachexia and suggests that maintaining mitochondrial redox homeostasis may represent a novel therapeutic strategy.
METHODS AND RESULTS: We investigated the role of cancer cell-derived exosomes in metabolic alterations of skeletal muscle cells. Exosomes from a pro-cachectic renal carcinoma cell line (RXF393) induced myotube atrophy, enhanced mitochondrial ROS production, impaired mitochondrial respiration, and reduced expression of isocitrate dehydrogenase 2 (IDH2) and respiratory chain complex subunits compared to observations in non-cachectic controls. miRNA profiling identified enrichment of miR-1260b in pro-cachectic exosomes, and transfection with a miR-1260b mimic reproduced these phenotypes, including IDH2 downregulation, impaired antioxidant defense, and mitochondrial dysfunction.
CONCLUSION: These findings demonstrate that cancer-derived exosomal miR-1260b suppresses IDH2, disrupts mitochondrial redox balance, and promotes muscle wasting. This study reveals a mechanistic link between exosomal miRNAs and mitochondrial dysfunction in cancer cachexia and suggests that maintaining mitochondrial redox homeostasis may represent a novel therapeutic strategy.