Wired ran a news report about a Science paper showing how mitochondria are culprits in making heart cells dysfunction. I wondered about brain cells. After all, brain cells need energy too. What about brain cell mitochondria?
Now, the Wired report caught my eye because it was about heart cells, and I generally follow cardiac regeneration research. For instance, say you have a heart attack — blood is cut off to part of your heart, and that tissue dies. If you later activate cardiac stem cells, found in little pockets in the heart, or if you mobilize your own stem cells to home into the heart, or if you take your stem cells out, juice them up a little, and add them back, you may be able to regrow that dead tissue, good as new. This seems a little Frankensteinian, but here is a PUBMED search on cardiac + stem cell, and you can peruse the reports.
Exemplar mitochondrial DNA dispersion agent: Mother
So that’s why I was interested in this mitochondria study — because of the cardiac aspect. But what about mitochondria and brain tissue?
Many brain-related conditions are X-chromosome linked, like Fragile X and the Fragile X pre-mutation. And there’s mitochondrial DNA. Mitochondrial DNA is usually maternally inherited, unless you are a bivalve or something. People get their mitochondrial DNA straight from their biological mothers — no combining with the DNA from biological dad. So even if Mom is diminutive, her mitochondria better be strong enough to last through whatever damage you put it through in your lifetime, hopefully, of clean livin’. If mitochondrial DNA gets wobbly, there goes the mitochondria — the cells’ internal energy machinery.
So here are two papers: One on mitochondria + serotonin, and the other on mitochondria + dopamine.
First, what does serotonin do for mitochondria? It stimulates transport down the axon. Interestingly, the authors say:
. . .Administration of a 5-HT1A receptor antagonist inhibited mitochondrial movement, whereas addition of fluoxetine, a selective serotonin reuptake inhibitor, promoted mitochondrial movement. . . .
So what does that say about appetite suppressants like the phen-fens-without-the-heart-problems, such as lorcaserin (discussed here and here and here)? It looks like mitochondria transport may be the key for energy distribution to cut appetite via the serotonin receptors.
Now for dopamine. There’s a lot of research on dopamine in neurodegenerative diseases, like Parkinsons’. Other researches investigate what dopamine does to neurons in non-neurodegenerative diseases — like schizophrenia. What does dopamine do where there’s no neurodegeneration?
Dopamine apparently doesn’t kill the mitochondria (or the cell) but it beats it up the mitochondrial energy transport machinery pretty badly. (Compare George Carlin’s description of Mohammed Ali, here starting at 4:20, I won’t give away the punchline at about 4:45-5:00). The researchers note a dysfunction in schizophrenia between dopamine and mitochondria complex 1 (the first enzyme that transfers electrons as part of mitochondria’s energy-making machinery).
So, serotonin, in effect, turbo charges mitochondrial transport — speeding up electron transfer and energy use. Interesting. I wonder if this is part of why people lose weight on lorcaserin without changing diet or exercise (according to reports). After all, serotonin goes to a variety of tissues, not just the brain.
Dopamine, in those possibly having a particular form of mitochondrial enzyme, Complex 1, may inhibit electron transport and energy use in the cell by clogging up the mitochondria so the energy machinery is stuck.
So, perhaps the good thing about having a blog and not even pretending to be a scientist is that I can speculate so here goes: this is the reason some psych meds cause weight gain. Perhaps adding a little complex 1 or a dopmanine agonist that is a little twisted around to not bind to complex 1 would be a good drug candidate.
(Don’t worry drug co’s, this is totally not enabled, and won’t spoil any patents).
Just a note: I’m feeling a little like a faker because I’m not a scientist, but I’m posting with the Research Blogging logo and approval. It is difficult to even get started on a post because I know that if I were clicking through powerpoints , I’d be totally trashed by a learned audience. That’s probably the most difficult thing about writing any post — remembering that this is only a blog, and hopefully this blog with some of my more outré speculation is doing a little bit to add to advance the neuro-ball, so to speak. Or just watch the Parle a ma main video like everyone else.
Fan, W., Waymire, K.G., Narula, N., Li, P., Rocher, C., Coskun, P.E., Vannan, M.A., Narula, J., MacGregor, G.R., Wallace, D.C. (2008). A Mouse Model of Mitochondrial Disease Reveals Germline Selection Against Severe mtDNA Mutations. Science, 319(5865), 958-962. DOI: 10.1126/science.1147786
BRENNERLAVIE, H., KLEIN, E., ZUK, R., GAZAWI, H., LJUBUNCIC, P., BENSHACHAR, D. (2008). Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex I: Relevance to dopamine pathology in schizophrenia. Biochimica et Biophysica Acta (BBA) – Bioenergetics, 1777(2), 173-185. DOI: 10.1016/j.bbabio.2007.10.006
CHEN, S., OWENS, G., CROSSIN, K., EDELMAN, D. (2007). Serotonin stimulates mitochondrial transport in hippocampal neurons. Molecular and Cellular Neuroscience, 36(4), 472-483. DOI: 10.1016/j.mcn.2007.08.004
Mol Cell Neurosci. 2007 Dec;36(4):472-83. Epub 2007 Aug 15
Serotonin stimulates mitochondrial transport in hippocampal neurons.
The Neurosciences Institute, 10640 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Axonal transport of mitochondria is critical for proper neuronal function. However, little is known about the extracellular signals that regulate this process. In the present study, we show that the neuromodulator serotonin (5-HT) greatly enhances mitochondrial movement in the axons of rat hippocampal neurons in vitro. Administration of a 5-HT1A receptor antagonist inhibited mitochondrial movement, whereas addition of fluoxetine, a selective serotonin reuptake inhibitor, promoted mitochondrial movement. 5-HT receptors are known to activate the Akt/Protein kinase B pathway. Consistent with this, directional mitochondrial movement was almost completely blocked by a specific Akt inhibitor. Moreover, an inhibitor of glycogen synthase kinase-3beta (GSK3beta), a kinase whose activity is blocked by Akt-mediated phosphorylation, promoted mitochondrial movement. These findings show that 5-HT1A receptor activation stimulates mitochondrial movement in hippocampal neurons by inhibiting GSK3beta activity via Akt. Our findings suggest that 5-HT may mediate the redistribution of energy sources within responsive neurons, a possibility that has significant implications for understanding the global biological effects of this important neuromodulator.
PMID: 17904380 [PubMed - indexed for MEDLINE]
Biochim Biophys Acta. 2008 Feb;1777(2):173-85. Epub 2007 Oct 23
Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex I: Relevance to dopamine pathology in schizophrenia.
Brenner-Lavie H, Klein E, Zuk R, Gazawi H, Ljubuncic P, Ben-Shachar D.
Research Lab of Psychobiology, Department of Psychiatry – Rambam Medical Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Deleterious effects of dopamine (DA) involving mitochondrial dysfunction have an important role in DA-associated neuronal disorders, including schizophrenia and Parkinson’s disease. DA detrimental effects have been attributed to its ability to be auto-oxidized to toxic reactive oxygen species. Since, unlike Parkinson’s disease, schizophrenia does not involve neurodegenerative processes, we suggest a novel mechanism by which DA impairs mitochondrial function without affecting cell viability. DA significantly dissipated mitochondrial membrane potential (Deltapsi(m)) in SH-SY5Y cells. Bypassing complex I prevented the DA-induced depolarization. Moreover, DA inhibited complex I but not complex II activity in disrupted mitochondria, suggesting complex I participation in DA-induced mitochondrial dysfunction. We further demonstrated that intact mitochondria can accumulate DA in a saturated manner, with an apparent K(m)=122.1+/-28.6 nM and V(max)=1.41+/-0.15 pmol/mg protein/min, thereby enabling the interaction between DA and complex I. DA accumulation was an energy and Na(+)-dependent process. The pharmacological profile of mitochondrial DA uptake differed from that of other characterized DA transporters. Finally, relevance to schizophrenia is demonstrated by an abnormal interaction between DA and complex I in schizophrenic patients. These results suggest a non-lethal interaction between DA and mitochondria possibly via complex I, which can better explain DA-related pathological processes observed in non-degenerative disorders, such as schizophrenia.
PMID: 17996721 [PubMed - in process]
Comments