NEW YORK (Reuters Health) - Genes encoding mitochondrial proteins and that regulate oxidative phosphorylation and the ATP-dependent process of proteasome degradation are significantly down-regulated in the brains of patients with bipolar disorder, researchers at Harvard Medical School report.
This suggests that the symptoms of bipolar disorder result from reduced energy capacity and inadequate cellular responses to stress, lead investigator Dr. Christine Konradi told Reuters Health.
Previous research has implicated abnormal mitochondrial energy metabolism in bipolar disorder. Dr. Konradi and associates performed gene expression profiling on RNA extracted from the hippocampal sections obtained postmortem, reporting their findings in the Archives of General Psychiatry for March.
Mortality had been due to heart disease, organ failure, infection or cancer. There was only one suicide among the nine subjects with bipolar disorder, and none among the eight with schizophrenia and 10 healthy control subjects. Diagnoses were verified by review of medical records and interviews with family members of the brain donors.
The expression of nuclear mRNA coding for mitochondrial proteins was significantly decreased in subjects with bipolar disorder compared with control subjects, but not in subjects with schizophrenia. There were 43 genes with expression reduced at least 1.2-fold, 18 of which code for mitochondrial proteins, the report indicates. Others are involved in energy metabolism, protein degradation, and neurotransmission.
The Boston-based team selected four genes with decreased expression in the hippocampus and found that they were also down-regulated in the frontal cortex of subjects with bipolar disorder.
They suggest that the number of mitochondria per neuron may be reduced or that “a subset of neurons with high mitochondrial numbers (eg, GABAergic interneurons) is lost.” If mitochondrial dysregulation shifts metabolism toward anaerobic energy production, there could be concomitant increases in reactive oxygen species, glutamate excitotoxicity, and apoptosis in the brain, the authors add.
These findings “play into the idea that bipolar disorder is a problem with stress responses,” Dr. Konradi said. “If the brain is already running on empty, there may be no energy reserves that can be called on in times of stress.”
For example, the neurotransmitter glutamate released in response to stimulation is rapidly transported back into the cell in normal subjects. Low energy stores could inhibit the process of “pumping glutamate back into glial cells and neurons,” increasing the risk of neurotoxicity, she explained.
The authors suggest that the changes are not due to medications patients were taking. “If the genes for mitochondrial respiration were down-regulated as a result of antipsychotic drug treatment, this effect should have been more pronounced in the subjects with schizophrenia, who were treated with higher doses of antipsychotic drugs,” they write.
Dr. Konradi now hopes to examine peripheral tissue, such as muscle and white blood cells, to see if the same genetic pattern exists there. Ultimately, this information could lead to new diagnostic tests and medications to “boost mitochondrial energy in the brain.”
Source: Arch Gen Psychiatry 2004;61:300-308. [ Google search on this article ]
MeSH Headings:Energy Metabolism: Genetic Techniques: Interneurons: Investigative Techniques: Polymerase Chain Reaction: Gene Expression Profiling: Analytical, Diagnostic and Therapeutic Techniques and EquipmentCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.