From iPSCs to NPCs to cortical neurons: bioenergetic, neuronal, and calcium signaling phenotypes in bipolar disorder with and without familial mitochondrial disease

Background Psychiatric disorders frequently accompany primary mitochondrial diseases (PMDs), implicating mitochondrial dysfunction as a shared biological substrate for psychiatric vulnerability. To determine how familial mitochondrial risk influences neuronal development in bipolar disorder (BD), we generated induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs), and cortical neurons (CNs) from three healthy controls (CT), three patients with BD, and three patients with BD and a family history of mitochondrial disease (BD-FMD).

Across differentiation, we assessed mitochondrial function (ATP production, mitochondrial membrane potential, ROS generation, cytosolic cell-free mtDNA), metabolomic signatures, calcium imaging, and neuronal electrophysiological activity through multi-electrode arrays (MEA).

BD neurons uniquely exhibited pronounced hyperexcitability in comparison to CT and BD-FMD groups. The BD-FMD group displayed prolonged mitochondrial calcium transients, altered membrane potential, and aberrant ROS, in comparison to CT and BD, consistent with a sustained energetic deficit. Metabolomic profiling revealed distinct pathway enrichments in BD and BD-FMD, indicating divergent bioenergetic adaptations to mitochondrial burden.

Our findings reveal that familial mitochondrial liability actively reshapes neuronal differentiation and function, producing distinct trajectories of mitochondrial performance, calcium signaling, and network excitability. These results suggest that mitochondrial dysfunction in BD is not a secondary byproduct of illness, but a mechanistic contributor to altered neuronal energetics and communication. Together, these findings delineate how inherited mitochondrial vulnerability reshapes neuronal excitability and metabolism, revealing bioenergetic phenotypes that may inform precision stratification and therapeutic targeting in BD. Competing Interest Statement The authors have declared no competing interest.