When Brain Cells Run Low on Power: New Clues to the Biology of Bipolar Disorder

Bipolar disorder has long been understood through the lens of mood swings and brain chemistry, but a new study published in Nature Communications points to something more fundamental happening inside neurons: a breakdown in how they manage their energy supply. Researchers studying lab-grown neurons and mouse models found that cellular power plants — mitochondria — may behave abnormally in ways that could help explain the unstable communication between brain cells seen in bipolar disorder.

Mitochondria on the Move

Mitochondria don't just sit passively inside cells; they travel along the long, thin extensions of neurons called axons, stopping at synapses (the junctions where neurons pass signals to one another) to supply energy and help manage calcium levels needed for communication. In this study, the research team used neurons derived from stem cells donated by people with bipolar disorder and observed that these mitochondria moved unusually often, shuttling in and out of synaptic terminals more frequently than typical. This constant movement meant fewer mitochondria stayed anchored where they were needed most.

The consequence, according to the researchers, was that synaptic terminals had a harder time maintaining stable energy supplies and calcium regulation. This didn't necessarily weaken the average strength of synaptic signals, but it did make those signals more erratic and unpredictable — a pattern that could plausibly contribute to the instability of mood and behavior associated with bipolar disorder, though the study does not claim this directly causes the condition in humans.

A Genetic Link and a Missing Anchor

To explore why this mitochondrial restlessness occurs, the team looked at AKAP11, a gene already associated with increased genetic risk for bipolar disorder. When they reduced AKAP11 activity in mouse neurons, the same energy-related synaptic problems appeared, reinforcing a potential connection between this known risk gene and the mitochondrial behavior observed in the human stem-cell-derived neurons.

The researchers also identified reduced levels of a protein called syntaphilin (SNPH) in neurons from people with bipolar disorder. SNPH acts like a molecular anchor, helping keep mitochondria docked at synapses instead of drifting away. When the scientists removed the gene for SNPH in mice altogether, the animals displayed behaviors resembling mania — one of the hallmark states of bipolar disorder. This strengthens the idea that insufficient mitochondrial anchoring at synapses may be tied to manic-like symptoms in animal models.

Lithium's Familiar Role, Seen From a New Angle

Perhaps the most striking part of the study involves lithium, a medication that has been used for decades to help manage bipolar disorder despite scientists still not fully understanding how it works. In this research, lithium treatment helped restore the normal anchoring of mitochondria at synapses, improved the neurons' ability to maintain stable energy levels, reduced the erratic synaptic activity observed earlier, and reversed the manic-like behaviors in the SNPH-deficient mice.

This doesn't mean lithium's therapeutic effects in people are fully explained by this single mechanism, but it does offer a compelling new piece of the puzzle: a possible cellular pathway through which this long-used treatment might exert some of its stabilizing effects.

From Petri Dish to Patient

The findings come from laboratory models — stem-cell-derived neurons and genetically modified mice — not from direct observation of living human brains. The associations between mitochondrial behavior, the AKAP11 and SNPH genes, and bipolar-like symptoms are compelling, but they represent evidence of biological links rather than proof that faulty mitochondrial anchoring alone causes bipolar disorder in humans. Human mood disorders are complex and shaped by many genetic, environmental, and psychological factors.

Still, this research adds an intriguing dimension to our understanding of bipolar disorder, suggesting that problems with how brain cells manage and stabilize their internal energy resources might play a meaningful role alongside more traditionally studied neurochemical factors. These findings are not a basis for changing treatment approaches, and anyone with questions about bipolar disorder, its treatment, or medications like lithium should consult their own physician or mental health professional for personalized guidance.

Source: Nature Communications, DOI: 10.1038/s41467-026-76722-x — Findings summarized from Li, Xiong, Li, and Sheng (2026), based on research conducted at the National Institute of Neurological Disorders and Stroke, NIH.