Research Frontiers

The Department of Psychiatry at the School of Medicine is advancing research based on the “mitochondrial dysfunction hypothesis” to uncover the pathology of bipolar disorder, a major psychiatric condition. Understanding the condition at the molecular level could revolutionize the diagnosis and treatment of psychiatric conditions traditionally categorized as mental illnesses. In this roundtable discussion, Professor Tadafumi Kato, Associate Professor Masaki Nishioka, and Specially Appointed Associate Professor Mie Kubota-Sakashita—who are approaching their research from an entirely novel perspective—examine the current state and future direction of psychiatry.

Clarifying the biological changes in the brain associated with bipolar disorder

―― Why did you choose bipolar disorder as your research topic?

Kato: In our department, we address a wide range of mental illnesses, including schizophrenia, mood disorders, stress-related disorders, sleep disorders, dementia, and developmental disorders. However, my primary motivation for conducting research comes from wanting to understand the pathology of bipolar disorder and use that knowledge to improve how we diagnose and treat it.

Bipolar disorder, along with schizophrenia, is one of the two major mental illnesses that is also among the most common. However, compared to other mental illnesses, research into bipolar disorder seems to be falling behind. A major reason is that genome analysis hasn’t progressed much, mainly because there’s a lack of patient data. To add to this, studies on neural circuits in the brain have been very limited.

――Why has research into bipolar disorder fallen behind in this sense?

Kato: When I first encountered a patient with bipolar disorder as a resident, I was struck by how someone in such a profound depressive state, unable to even move, could shift to mania the next day. This dramatic change convinced me that something significant was happening in the brain, driving me to start my research, and gave me the conviction that I could uncover the cause if I kept at it. While I initially hoped to compare a patient’s brain in their depressive and manic states using omics analysis, ethical and technical challenges made this approach difficult. However, it wasn’t as straightforward as I had hoped. Ideally, we could use omics analysis to compare the brain of a patient in a depressive state one day with their brain in a manic state the next, and that might immediately reveal the cause. But in reality, ethical and technical challenges make it difficult to study a patient’s brain at the molecular and cellular levels in this way. Fortunately, we’ve now uncovered significant clues about the underlying cause of this disorder, and taking the next steps in our research.

Specially Appointed Associate Professor Mie Kubota-Sakashita, Associate Professor Masaaki Nishioka, and Professor Tadafumi Kato (left to right)

――What areas are you concentrating your efforts in?

Kato: Since 2000, we have proposed the mitochondrial dysfunction hypothesis, supported by data showing that mitochondria, which play a role in regulating intracellular calcium, are involved in altering the brain function of patients with bipolar disorder. Based on this hypothesis, we are working on creating a mouse model, analyzing brain tissue from deceased patients, and performing genome analysis.

Kubota-Sakashita: My research focuses on investigating mitochondrial dysfunction in specific brain regions using mouse models and postmortem brains. While mitochondria are well-known for their role in energy production, they are equally critical for regulating calcium concentration in the brain, particularly at synapses, the sites where signals are transmitted between nerve cells. Calcium concentration has a direct impact on the efficiency of neurotransmitter release. When calcium levels increase, mitochondria rapidly absorb the excess calcium, helping to regulate the release of neurotransmitters like glutamate and serotonin.

However, when mitochondria fail to function properly, this calcium regulation is disrupted, impairing neurotransmission. To address this, I am also conducting research to identify compounds that can enhance the calcium-regulating capabilities of mitochondria.

Nishioka: My research is centered around two main pillars: genome analysis and single-cell analysis. I am especially focused on single-cell analysis, which has revolutionized the way we observe brain pathologies. It’s comparable to the transformative experience of using a submarine to illuminate the previously unseen depths of the pitch-black ocean. By understanding the unique properties of individual cells, I hope to uncover insights that will bring greater clarity to many aspects of brain disorders.

[Left] Single-nucleus RNA sequencing data from 41 thalamus samples were integrated and clustered, and visualized using UMAP. A total of 25 cell clusters were identified, of which cluster 15 correspond to PVT neurons.

――So, you’ve now shifted focus to the paraventricular thalamic nucleus?

Kato: Few research groups focus on specific brain regions in bipolar disorder studies. Most aim to identify subtle differences through comprehensive genome analysis or large-scale MRI studies involving thousands of patients. In contrast, our findings regarding the paraventricular thalamic nucleus provide insights that are not dependent on analyzing data from thousands of samples, bringing us closer to the core mechanisms of the disease. However, even though our hypothesis appears highly plausible to us, many others in the field do not view mental illnesses from this perspective. Our greatest challenge lies in persuading these individuals to consider this line of thought.

Nishioka: It’s undoubtedly a challenging issue. In scientific research, statistical significance is crucial, so determining the necessary sample size for reliable results is critical. However, the thalamus, the brain region we’re focusing on, is in a location that is difficult to access, even in postmortem brain tissue, which limits the ability to increase the sample size. If we were studying more accessible brain region, like the cortex, we could collect more substantial data. Unfortunately, the thalamus poses a much greater challenge for research.

A unique approach requires reliable data

――You mentioned that you will be conducting research with an eye toward clinical use. What exactly will that entail?

Kato: Our data strongly indicates the paraventricular thalamic nucleus as the key site of bipolar disorder. Moving forward, we aim to present this evidence to the broader scientific community and address skepticism about our theory.

Kubota-Sakashita: One of my ongoing research projects focuses on screening for such compounds. While some psychotropic drugs influence the calcium uptake function of mitochondria, this aspect has been largely overlooked because it has not been systematically studied. There is also potential to repurpose drugs developed for other conditions, but not yet marketed, if they prove effective in targeting mitochondrial dysfunction. My main research aim is to discover new mood stabilizers using an innovative screening method that centers on brain mitochondria.

Realizing genome-based personalized medicine
Bringing about a paradigm shift in psychiatry

―― What are some advantages of having your lab at Juntendo University?

Nishioka: A big advantage is the ability to verify the results of genome analysis using data from many patients, which was not possible at RIKEN.

Kubota-Sakashita: We are verifying the effectiveness of the screened compounds using iPS cells derived from patients with mitochondrial DNA mutations. At Juntendo University, we have the advantage of being able to obtain patient samples, and are also receiving technical training in iPS cell production through the cooperation of the Center for Genomics and Regenerative Medicine, which will support the success of our efforts. Although we are still in the early stages, I believe that cultivating miniature organs, known as organoids, will allow us to make even more significant discoveries.

――As a laboratory, what new goals are you working toward?

Kato: Our primary goal is to definitively establish the paraventricular thalamic nucleus as the cause of bipolar disorder and to develop a method for detecting mitochondrial dysfunction in this region within the next five years. We are also pursuing research into drug discovery, to create personalized treatment tailored to each patient’s condition. While molecular-targeted drug therapies based on genomic diagnosis are commonly used in cancer treatment, psychiatry lags behind by 10 or 20 years. We will continue our work with Dr. Nishioka and Dr. Kubota-Sakashita, to take the first step toward advancing psychiatry in a similar direction.

――That would bring about a major change in psychiatry, wouldn’t it?

Kato: Currently diagnosis in psychiatry primarily involves consultations based on conversation, with diagnoses made according to symptom classification, followed by medication prescriptions. This approach treats mental illnesses as disorders of the mind. However, as our understanding deepens and we recognize that mental illnesses are brain diseases, I believe that, in the future, mental illnesses will also be reclassified based on their pathology at the cellular and molecular levels, informed by genome analysis. While it may take some time to reach that point, I believe a significant paradigm shift in psychiatry is inevitable.