Mitochondria Genes
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Hi Dr. Phelps,
Just saw this on the CABF message board....Thought you might like to read it Thank YOu for your great work great work!!

Medications and other Treatments for BP
From: Martha (CABF)
Subject: Mitochondria (from Husseini Manji, M.D.)
Date: 1/7/2003 11:17:12 AM

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Mitochondria are organelles (within a cell) that generate the major molecule (ATP) by which cellular energy is transferred or spent. Think of them as the (rechargeable) batteries of the cell. ATP is used to "power" everything that the cell does--of interest to us, it is essential in the making of neurotransmitters, and also contributes to muscle tone.

Dr. Husseini Manji, Chief of the Laboratory of Molecular Pathophysiology at the NIMH, who is working on bipolar disorder, writes to us this morning:

"...just like not being a "classical" neurodegenerative disease, bipolar does not have many of the features of classic mitochondrial diseases, but I think that its quite plausible that we have an impairment of mitochondrial function.

"Its an area *very dear* to my heart (that's what bcl-2 [a neuroprotective protein enhanced by lithium and some other treatments that promotes cellular survival and protects the mitochondria, in particular, from apoptosis] mainly does for a living --regulate mitochondrial function), and it's undoubtedly involved in *treatment* and potentially at least in subgroups of bipolars. It's something we are investigating extensively in our  animal/cell studies, and getting geared up to do extensive human  studies (where we would simultaneously look at peripheral (blood cell  or skin) mitochondrial function directly, and at the same time do  brain imaging (MRS measures of lactate might be an indirect "readout" of the neurons' ability to handle loads/demands). This is one area  where I think at least some bipolars differ from unipolars -- I think  that bipolars may have an inherent impairment of what I call cellular  resilience, and therefore even normal loads are excessive and exact a  toll on the brain (is this why we see white matter hyperintensities in many young bipolars? (something "normally" associated with aging/cerebrovascular disease?))... *very recent* evidence suggests that mitochondria in nerve terminals also play an important role in regulating neurotransmitter release,  and so abnormalities could be associated not only with cell loss/atrophy/white matter hyperintensities, but also "moment to  moment" neurotransmitter release.

[Is this related to] mitochondrial *genes* (these are inherited only from  the mother) in bipolar disorder? -- I think that the current evidence is weak. However, I think that its pretty likely that we will find abnormal mitochondrial *function* in bipolars (as I mentioned, maybe a subset) -- could be due to abnormalities at any step in neurotrophic cascades which regulate bcl-2, some of its partners, the mitochondrial "pore", etc (doesn't need to be mitochondrial genes  themselves). These abnormalities would also explain the many, many findings of calcium abnormalities in blood cells in bipolars.

So its a *very important* area, and something we are pursuing preclinically and hopefully clinically soon.

Dear Ms. B' -- 
Thanks very much for passing that along.  Isn't it a great thing that somebody like Dr. Manji is taking the time to write to a "patients (and families)" bulletin board?!  I copied his letter into the section of my website on his work, as his personal expansion of those themes; and wrote to thank him.  So thank you for making that happen. 

Jim P. 

Published January, 2003


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