iPSC-derived cerebral organoids reveal mitochondrial, inflammatory and neuronal vulnerabilities in bipolar disorder
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.
Authors
- Alencar Kolinski Machado (ORCID: https://orcid.org/0000-0003-2003-8420)
- Ana C. Andreazza (ORCID: https://orcid.org/0000-0002-4323-7273)
- Angela Duong (ORCID: https://orcid.org/0000-0002-5856-3346)
- Delphine Ji
- Jaehyoung Choi (ORCID: https://orcid.org/0000-0001-5848-1036)
- Chiara C. Bortolasci (ORCID: https://orcid.org/0000-0002-0794-6363)
- Margaret Hahn (ORCID: https://orcid.org/0000-0001-8884-9946)
- George Nader (ORCID: https://orcid.org/0009-0009-9548-2869)
- Hyunjin Jeong (ORCID: https://orcid.org/0000-0003-4386-3845)
- Lauren Pappis (ORCID: https://orcid.org/0000-0003-0045-0768)
- Peter L. Carlen (ORCID: https://orcid.org/0000-0002-3339-8102)
- András Szatmári (ORCID: https://orcid.org/0000-0002-2402-8759)
- Erika Leigh Beroncal
- Bruna Panizzutti (ORCID: https://orcid.org/0000-0002-8825-734X)
- Ken R. Walder (ORCID: https://orcid.org/0000-0002-6758-4763)
- Dana El Soufi El Sabbagh (ORCID: https://orcid.org/0000-0001-8929-5586)
- Michael Berk (ORCID: https://orcid.org/0000-0002-5554-6946)
- Liliana Attisano (ORCID: https://orcid.org/0000-0003-4824-2642)
- Prathyusha Ravi Chander
Institutions
- University of Copenhagen (DK)
- Barwon Health (AU)
- University Health Network (CA)
- Centre for Addiction and Mental Health (CA)
- University of Toronto (CA)
- Universidade Franciscana (BR)
- Toronto Western Hospital (CA)
- Ontario Genomics (CA)
- Mitel (Canada) (CA)
Publication Details
- Journal
- Translational Psychiatry
- Published
- 2025-08-25
- DOI
- https://doi.org/10.1038/s41398-025-03529-7
- Citations
- 3
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
- Canadian Institutes of Health Research
- National Health and Medical Research Council