Mitochondrial Dysfunction in Bipolar Disorder with a Family History of Mitochondrial Disease: From Family Genetics to Patient-derived Induced Pluripotent Stem Cell-based Neuronal Models

Bipolar disorder (BD) is a complex mood disorder with high heterogeneity and unclear pathophysiology. Mitochondrial dysfunction has been repeatedly observed in BD; however, our understanding of mitochondrial dysfunction remains incomplete due to the lack of patient stratification, nuclear and mitochondrial genomics, and patient-derived neuronal models. The objective of this thesis was to investigate mitochondrial genetics and function in BD with or without a family history of mitochondrial disease. To achieve this, we (1) identified two families, each with at least one surviving member with BD and two deceased offspring with mitochondrial disease and BD patients without family history of mitochondrial disease; (2) performed nuclear and mitochondrial genome sequencing to evaluate family genetics and; (3) developed patient-derived induced pluripotent stem cell- (iPSC-) based neuronal models to uncover mitochondrial signatures specific to BD with a family history of mitochondrial disease. Nuclear and mitochondrial genome sequencing uncovered two novel variants in two genes, NUBPL and COMT, shared amongst BD across two unrelated families. While these variants require functional validation, we showed that bi-genomic sequencing could detect novel variants. Next, we generated patient-derived iPSCs and neural progenitor cells (NPCs). Grouping the family cases by the NUBPL and COMT variants, we identified that BD with a family history of mitochondrial disease presented lower maximal respiration in the iPSCs, higher proton leak and lower total ATP levels in NPCs compared to relatives. Furthermore, BD with a family history of mitochondrial disease presented lower glycolytic markers in the iPSCs than BD without a family history of mitochondrial disease. Our study demonstrates the importance of stratifying the heterogeneous BD patients into mitochondrial-based subgroups to unveil unique signatures of mitochondrial dysfunction. While single-cell models like iPSCs and NPCs offer insights into disease pathophysiology, there is a need to develop a disease model that recapitulates the complexity of the human brain. Therefore, we developed cerebral organoids (COs) from iPSCs derived from human peripheral blood mononuclear cells (PBMCs) and demonstrated preserved mitochondrial genetics and function across PBMCs to iPSCs to COs for the first time. These COs may serve as models to further investigate the role of mitochondrial dysfunction in BD.Ph.D