Minireview:Cell biological consequences of Leigh syndrome

Yıl 2011, Cilt: 3 Sayı: 1, 1 - 6, 01.01.2011

Felix Dıstelmaıer Peter Wıllems Jan Smeıtınk Werner Koopman Ertan Mayatepek

Öz

Mitochondria are double membrane-enveloped organelles that produce ATP in eukaryotic cells through the oxidative phosphorylation (OXPHOS) process. Accordingly, mitochondrial dysfunction is implicated in a broad range of human diseases, such as Parkinson's disease, Alzheimer's disease, cancer and diabetes. From a pediatric perspective, isolated malfunction of the first OXPHOS complex (complex I or NADH:ubiquinone oxidoreductase), is the most frequently observed defect. Complex I dysfunction may manifest itself as Leigh syndrome, which is an early-onset neurodegenerative disorder with a very poor prognosis. In addition to ATP generation, complex I dysfunction can also affect various other key cellular processes, like the generation of reactive oxygen species, maintenance of a sufficiently negative mitochondrial membrane potential, mitochondrial dynamics and calcium homeostasis. In the recent past, we performed a comprehensive live-cell analysis with skin fibroblasts from Leigh syndrome patients. These cells harbored nuclear-DNA encoded mutations in complex I subunits and displayed an isolated complex I deficiency. Here, we provide a brief overview of our key findings and directions for future research.

Anahtar Kelimeler

Mitochondria, oxidative phosphorylation, Leigh syndrome, treatment

Kaynakça

• Duchen M.R. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol. Aspects Med 2004; 25: 365-451.
• Chinnery PF, Turnbull DM. Epidemiology and treatment of mitochondrial disorders. Am J Med Genet. 2001; 106: 94-101. 3. Thorburn DR. Mitochondrial disorders: prevalence, myths and advances. J Inherit Metab Dis. 2004; 27: 349-62.
• Distelmaier F, Koopman WJ, van den Heuvel LP, Rodenburg RJ, Mayatepek E, Willems PH, et al. Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease. Brain. 2009; 132(Pt 4): 833-42.
• Vogel RO, Smeitink JA, Nijtmans LG. Human mitochondrial complex I assembly: a dynamic and versatile process. Biochim Biophys Acta. 2007; 1767: 1215-27.
• Fernandez-Moreira D, Ugalde C, Smeets R, Rodenburg RJ, Lopez-Laso E, Ruiz-Falco ML, et al. X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy. Ann Neurol. 2007; 61: 73-83.
• Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009; 417: 1-13.
• Verkaart S, Koopman WJH, van Emst-de Vries SE, Nijmans LGJ, van den Heuvel LWPJ.; Smeitink JAM, et al. Superoxide production is inversely related to complex I activity in inherited complex I deficiency. Biochim Biophys Acta 2007; 1772: 373-381.
• Verkaart S, Koopman WJH, Cheek J, van Emst- de Vries SE, van den Heuvel LWPJ, Smeitink JAM, et al. Mitochondrial and cytosolic thiol redox state are not detectably altered in isolated human deficiency. Biochim Biophys Acta. 2007; 1772 :1041-1051. oxidoreductase
• Komen JC, Distelmaier F, Koopman WJ, Wanders RJ, Smeitink J, Willems PH. Phytanic acid impairs mitochondrial respiration through protonophoric action. Cell Mol Life Sci. 2007; 64: 3271-3281.
• Distelmaier F, Koopman WJ, Testa ER, de Jong AS, Swarts HG, Mayatepek E, et al. Life cell quantification potential at the single organelle level. Cytometry A. 2008; 73: 129-38. membrane
• Distelmaier F, Visch HJ, Smeitink JA, Mayatepek E, Koopman WJ, Willems PH. The antioxidant Trolox potential and Ca2+ -stimulated ATP production in human complex I deficiency. J Mol Med. 2009;87: 515-22. membrane
• Brookes PS. Mitochondrial H+ leak and ROS generation: an odd couple. Free Radic Biol Med. 2005; 38: 12-23.
• Koopman WJH, Verkaart S, Visch H, van Emst- de Vries SE, Nijtmans LGJ, Smeitink JAM, et al. Human deficiency: radical changes in mitochondrial morphology? Am J Physiol Cell Physiol. 207; 293: C22-C29. oxidoreductase
• Visch HJ, Koopman WJ, Leusink A, van Emst-de Vries SE, van den Heuvel LP, Willems PH, et al. Decreased agonist-stimulated mitochondrial ATP production caused by a pathological reduction in endoplasmic reticulum calcium content in human complex I deficiency. Biochim Biophys Acta. 2006; 1762: 115-123.
• Valsecchi F, Esseling JJ, Koopman WJ, Willems PH. Calcium and ATP handling in human NADH:ubiquinone oxidoreductase deficiency. Biochim Biophys Acta. 2009;1792: 1130-7.
• Landolfi B, Curci S, Debellis L, Pozzan T, Hofer AM. Ca2+ homeostasis in the agonist-sensitive internal store: functional interactions between mitochondria and the ER measured In situ in intact cells. J Cell Biol 1998; 142: 1235-1243.
• Visch HJ, Rutter GA, Koopman WJ, Koenderink JB, Verkaart S, de Groot T, et al. Inhibition of mitochondrial agonist-induced ATP production and Ca2+ handling in human complex I deficiency. J Biol Chem. 2004; 279: 40328-40336. restores
• Visch HJ, Koopman WJ, Zeegers D, van Emst-de Vries SE, van Kuppeveld FJ, van den Heuvel LP, et mitochondrial ATP production to accelerate agonists increase mitochondrial [Epub ahead of print] complex I
• Smeitink JAM, Zeviani M, Turnbull DM, Jacobs HT. Mitochondrial medicine: a metabolic perspective on the pathology of oxidative phosphorylation disorders. Cell Metab. 2006; 3: 9-13.
• Koene S, Smeitink J. Mitochondrial medicine: entering the era of treatment. J Intern Med. 2009; 265: 193-209.
• Koopman WJ, Verkaart S, van Emst-de Vries SE, Grefte S, Smeitink JA, Nijtmans LG, et al. Mitigation of NADH: Ubiquinone oxidoreductase deficiency by chronic Trolox treatment. Biochim Biophys Acta. 2008; 1777: 853-859.