Manganese Health Research Program: Phase 2, Core 9

Research Core Project:
A study of the nervous system in welders

Core Principal Investigator:
Dag G Ellingsen
National Institute of Occupational Health
P.O. Box 8149 Dep
N-0033 Oslo, Norway
dag.ellingsen@stami.no

Key collaborators:
Valery Chashchin
Northwest Public Health Research Centre
St. Petersburg, Russia

Project objectives:

To determine whether Mn2+ interferes with Ca2+ activation of pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (ICDH) a-ketoglutarate dehydrogenase (aKGDH) or the F1F0 ATP synthase and decreases the rate of Ca2+-stimulated ATP production using oxidation rate experiments.
To determine whether Mn2+ can inhibit mitochondrial ETC complex 1 using oxidation rate experiments.
To characterize the effect of Mn2+ on ATP production, ROS production, and cell death in neuronal cell lines in the presence of factors known to produce signs of PSN in animals.

New publications:

Brookes, P.S., N. Parker, J. A. Buckingham, A. Vidal-Puig, A. P. Halestrap, T. E. Gunter, D. G. Nicholls, P. Bernardi, J. J. Lemasters, and M. D. Brand. UCP’s - Unlikely calcium porters. Nature Cell Biol. 11: 1235 - 1237, 2008.
Gunter, T. E. and S.-S. Sheu. Characteristics and possible functions of mitochondrial Ca2+ transport mechanisms. Biochem. Biophys. Acta Bioenergetics (In Press) 2009.
Gunter, T. E., C. E. Gavin, and K. K. Gunter. The case for manganese interaction with mitochondria. Neurotoxicology (In Press) 2009.

We also have another publication, almost ready for submission, describing induction of reactive oxygen species via Mn nanoparticles which seems to represent another mechanism of Mn-induced cell death and free radical production. It also compares the effects of Mn nanoparticles with those of other metal/metal oxide nanoparticles. It is :
Van Winkle, B. A., K. L. Bentley, J. M. Malecki, K. K. Gunter, I. M. Evans, A. Elder, J. N. Finkelstein, G. Oberdorster, and T. E. Gunter. Nanoparticle uptake by type 1 alveolar epithelial cells and their oxidant stress response. (to be submitted).

Project description:

Earlier work in our laboratory has used x-ray spectroscopic techniques to show that no observable manganese3+ (Mn3+) is produced by oxidation of Mn2+ in brain mitochondria, neuron-like cells or astrocytes. This has led us to hypothesize that the proximal cause or causes of Mn toxicity are either transport of Mn3+ into the target tissue or damage by Mn2+. As is discussed in the Background, we believe that possible damage by Mn2+ is likely to be particularly important in explaining how Mn can act as a risk factor in Parkinsonism (PSM). Mn2+ is known to bind to all Ca2+ binding sites with an affinity as strong as Ca2+’s or stronger (see Table 1). In mitochondria the rate of ATP production can be increased by a factor of up to three by binding of Ca2+ to a set of dehydrogenases associated with the Krebs or TCA cycle and to the mitochondrial ATP synthase1-3. Mn2+ binding to these sites of Ca2+ activation of ATP production could inhibit the activation and greatly decrease the ATP that can be produced in the high energy requiring cells of the target tissue. We show in the Preliminary Data that this does occur at a-ketoglutarate dehydrogenase (a KGDH). Since a decrease in metabolic energy production has been postulated as a possible cause of PSM4-7, Mn2+ in the substantia nigra pars compacta (SNpc) and striatum, the target tissues for PSM, could be a factor in the development of PSM.
Furthermore, as is discussed in the Background, inhibitors of the mitochondrial electron transport chain (ETC) complex I show a particularly close relationship to the development of PSM, and in some cases have been shown to induce signs and symptoms indistinguishable from those of idiopathic Parkinson’s disease in humans, rats, and mice8-11. We present arguments which suggest that Mn2+ might also function as an inhibitor of complex I. If it does function in this way, it is very likely that it contributes to the development of PSM. We have therefore suggested and now hypothesize two ways in which Mn2+ could function to increase the risk of development of PSM: 1) by decreasing the supply of ATP in energy demanding cells, and 2) by functioning as a complex I inhibitor, a stress which has been closely connected to the development of PSM. We propose 3 specific aims to test these hypotheses and to characterize the effects of Mn2+ on dopaminergic neurons and astrocytes under conditions related to those in which development of PSM occurs.

Project status
Project started: 1. February 2007

Anticipated completion: 31. December 2010

Key research accomplishments

The study was finally approved on October 20, 2006, by the appropriate regional ethical committee in Norway (The Regional Committee for Medical Research Ethics, Southern Norway (REK Sør)).

The study was finally approved on December 25, 2006, by the appropriate ethical committee in Russia (I.P.Pavlov State Medical University- St. Petersburg).

A final approval of the project protocol by the DOD was received on January 16, 2007.

A contract was signed between the National Institute of Occupational Health (Norway) and Vanderbilt University (USA) on January 31, 2007.

All preparations have been finalized before data collection can start.

Last updated: October 02, 2007