David Haschka1, Chiara Volani1, Ambra Stefani2, Piotr Tymoszuk1, Thomas Mitterling2,3, Evi Holzknecht2, Anna Heidbreder2,4, Stefan Coassin5, Zuzana Sumbalova6, Markus Seifert1, Stefanie Dichtl1, Igor Theurl1, Erich Gnaiger7, Florian Kronenberg5, Birgit Frauscher2, Birgit Högl2, Guenter Weiss1,8. 1. Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria. 2. Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. 3. Department of Neurology, Wagner-Jauregg Hospital Linz, Linz, Austria. 4. Department of Neurology, Division of Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Muenster, Germany. 5. Department of Medical Genetics, Division of Genetic Epidemiology, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. 6. Pharmacobiochemical Laboratory of the 3rd Department of Internal Medicine, Faculty of Medicine in Bratislava, Comenius University, Bratislava, Slovakia. 7. Department of General and Transplant Surgery, D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria. 8. Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria.
Abstract
BACKGROUND: Restless legs syndrome is a sensorimotor neurological disorder of the limbs that impairs quality of life and disturbs sleep. However, there has been progress in understanding the disease involving the dopaminergic system as well as iron metabolism. The exact pathophysiological mechanisms of restless legs syndrome remain elusive. We tried to elucidate the underlying mechanisms in iron metabolism in restless legs syndrome subjects on a systemic, cellular, and mitochondrial level. METHODS: We conducted a study prospectively recruiting 168 restless legs syndrome patients and 119 age-matched healthy controls focusing on iron metabolism using human monocytes as surrogates. RESULTS: Evaluation of systemic iron metabolism parameters in the circulation showed no significant difference between patients and controls. We observed a significant reduction in mRNA levels of heme oxygenase 1 and mitochondrial iron genes like mitoferrin 1 and 2 in monocytes isolated from restless legs syndrome patients, indicating mitochondrial iron deficiency. Interestingly, we also observed reduced expression of iron regulatory protein 2 along with impaired activity of mitochondrial aconitase and reduced mitochondrial superoxide formation in restless legs syndrome subjects. Along this line, patients had reduced mitochondrial respiratory capacity that improved in restless legs syndrome subjects under treatment with dopaminergic drugs compared with untreated patients. CONCLUSIONS: Our data suggest that restless legs syndrome is linked to mitochondrial iron deficiency and associated impairment of mitochondrial function. This is partly corrected by treatment with dopaminergic drugs compared with untreated patients, which may be linked to an effect of dopamine on cellular iron homeostasis.
BACKGROUND: Restless legs syndrome is a sensorimotor neurological disorder of the limbs that impairs quality of life and disturbs sleep. However, there has been progress in understanding the disease involving the dopaminergic system as well as iron metabolism. The exact pathophysiological mechanisms of restless legs syndrome remain elusive. We tried to elucidate the underlying mechanisms in iron metabolism in restless legs syndrome subjects on a systemic, cellular, and mitochondrial level. METHODS: We conducted a study prospectively recruiting 168 restless legs syndrome patients and 119 age-matched healthy controls focusing on iron metabolism using human monocytes as surrogates. RESULTS: Evaluation of systemic iron metabolism parameters in the circulation showed no significant difference between patients and controls. We observed a significant reduction in mRNA levels of heme oxygenase 1 and mitochondrial iron genes like mitoferrin 1 and 2 in monocytes isolated from restless legs syndrome patients, indicating mitochondrial iron deficiency. Interestingly, we also observed reduced expression of iron regulatory protein 2 along with impaired activity of mitochondrial aconitase and reduced mitochondrial superoxide formation in restless legs syndrome subjects. Along this line, patients had reduced mitochondrial respiratory capacity that improved in restless legs syndrome subjects under treatment with dopaminergic drugs compared with untreated patients. CONCLUSIONS: Our data suggest that restless legs syndrome is linked to mitochondrial iron deficiency and associated impairment of mitochondrial function. This is partly corrected by treatment with dopaminergic drugs compared with untreated patients, which may be linked to an effect of dopamine on cellular iron homeostasis.
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