El Soufi El Sabbagh Dana, Kolinski Machado Alencar, Pappis Lauren, Leigh Beroncal Erika, Ji Delphine, Nader George, Ravi Chander Prathyusha, Choi Jaehyoung, Duong Angela, Jeong Hyunjin, Panizzutti Bruna, Bortolasci Chiara Cristina, Szatmari Andrea, Carlen Peter, Hahn Margaret, Attisano Liliana, Berk Michael, Walder Ken, Andreazza Ana Cristina
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
Krembil Brain Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
Transl Psychiatry. 2025 Aug 25;15(1):315. doi: 10.1038/s41398-025-03529-7.
Bipolar disorder (BD) is increasingly recognized as a disease with both mitochondrial dysfunction and heightened inflammatory reactivity, yet contribution to neuronal activity remains unclear. To address these gaps, this study utilizes iPSC-derived cerebral organoids (COs) from BD patients and healthy controls to model disease-specific metabolic and inflammatory dysfunction in a more physiologically relevant system. BD COs exhibited mitochondrial impairment, dysregulated metabolic function, and increased nod-leucine rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome activation sensitivity. Treatment with MCC950, a selective NLRP3 inhibitor, effectively rescued mitochondrial function and reduced inflammatory activation in both BD and control COs. The effect of a Bioactive Flavonoid Extract (BFE), a potential therapeutic, was also explored and yielded a partial rescue of inflammasome activation. These findings highlight a mitochondria-inflammasome axis in BD pathophysiology and establish a novel platform for studying BD-associated cellular mechanisms, ultimately bridging the gap between molecular dysfunction and therapeutic development.
双相情感障碍（BD）越来越被认为是一种兼具线粒体功能障碍和炎症反应增强的疾病，但其对神经元活动的影响仍不明确。为填补这些空白，本研究利用来自BD患者和健康对照的诱导多能干细胞衍生的脑类器官（COs），在一个生理相关性更强的系统中模拟疾病特异性的代谢和炎症功能障碍。BD脑类器官表现出线粒体损伤、代谢功能失调以及富含亮氨酸重复序列和吡啉结构域的蛋白3（NLRP3）炎性小体激活敏感性增加。用选择性NLRP3抑制剂MCC950治疗可有效挽救BD和对照脑类器官的线粒体功能并减少炎症激活。还探索了一种具有潜在治疗作用的生物活性黄酮提取物（BFE）的效果，结果显示其可部分挽救炎性小体激活。这些发现突出了BD病理生理学中的线粒体-炎性小体轴，并建立了一个研究BD相关细胞机制的新平台，最终弥合分子功能障碍与治疗开发之间的差距。
