The Cellular Bipolar Breakdown Lane

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Science
The Cellular Bipolar Breakdown Lane

Is the mitochondria responsible?

by John McManamy

Is bipolar disorder the result of a mitochondrial malfunction? Wait! What on earth are mitochondria? Funny you should ask. Mitochondria are specialized organelles in the cell vital to the production of cellular energy. Sugar is broken down in the cytoplasm by a process known as glycolosis to produce ATP, then pyruvate. The pyruvate then enters the mitochondrion, where it is further sliced and diced to kickstart a complex chemical reaction you may vaguely recall from high school biology called the Krebs cycle. The stripped-away electrons from the Krebs cycle are coupled with oxygen in the inner mitochondrial membrane that result in the release of chemical energy in the form of ATP.

"If any part of a human cell truly contains what the ancients called the fire of life," says biologist Kenneth Miller PhD of Brown University, "it's the mitochondrion. Interrupt, even for a moment, the flow of electrons to oxygen, and that fire will go out." The poison cyanide acts by blocking mitochondrial electron transport, which explains why it is so deadly. Can bipolar disorder have a similar, albeit more subtle, effect?

In 2000, Tadafumi Kato MD and Nobumasa Kato MD, PhD of the University of Tokyo proposed the mitochondrial dysfunction hypothesis based, among other things, on abnormal brain energy metabolism in bipolar patients measured by MRS scans and mitochondrial depletion in autopsied bipolar brains. Their search for mutant mitochondrial DNA turned up two suspect genes.

In an article in the March 2004 Archives of General Psychiatry, Christine Konradi PhD and her colleagues at Harvard and McLean Hospital report on a breakthrough study that may place the humble mitochondrion front stage center in bipolar research. Postmortem tissue samples were extracted from the hippocampi of the brains of nine individuals with bipolar disorder, eight with schizophrenia, and 10 healthy controls. The hippocampus attracted the investigators’ interest, as it is an area in the brain where neurogenesis (new brain cell growth) takes place, as well as being involved in short term memory and emotion. Moreover, there is evidence from brain imaging that the hippocampus functions differently in bipolar patients and in schizophrenia.

The researchers used gene array technology to determine how 12,558 nuclear genes switched on or off proteins in the hippocampus, finding that the expression of 43 were decreased in the bipolar sample but not a single gene in the schizophrenia group. Of these 43 genes, 18 coded for mitochondrial proteins involving several chemical processes. The authors theorize that gene mutations are at best only a partial explanation for their findings, that bipolar disorder may result in reduced numbers of mitochondria in the neuron or that selective neurons are lost. Alternatively, various mechanisms that control DNA transcription may affect gene expression.

Significantly, even though it was a small study and there was some variation in the brains, all the bipolar brains "seemed to have the same pattern," Dr Konradi told this writer. This indicates that mitochondrial malfunction may affect all of us rather than just a small subset of patients, further suggesting obvious places to look for new treatments. There are no meds for mitochondrial disorders, but Dr Konradi reported that "if our findings are reproduced, it should be quite an incentive for the pharmaceutical industry to come up with something."

Meanwhile, also at McLean Hospital, researchers are on the case. In June 2004, Repligen Corp announced the results of a phase I open study conducted by a different team at the facility. Nineteen unipolar and bipolar depressed patients were safely treated with the experimental drug RG2133. The drug metabolizes to uridine, which is essential to the synthesis of DNA and RNA and is synthesized in the mitochondria. The company plans phase II trials later this year for both depression and bipolar.
Update June 2, 2005

A Cleveland Clinic survey of 38 outpatients with mitochondrial diseases found 70 percent met the criteria for major mental illness, including 54 percent with lifetime depression, 17 percent with lifetime bipolar, 11 percent with lifetime panic, and 11 percent with current generalized anxiety. On average, the mitochondrial disease was diagnosed 4.5 years after the onset of psychiatric symptoms and 14 years after a physician was seen.

Updated June 2, 2005, reviewed Feb 11, 2008