Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention
| Autor: | Albert Quintana, Judith Homberg, Merel J. W. Adjobo-Hermans, Mariusz R. Wieckowski, Sander Grefte, Melissa van de Wal, Jaap Keijer, Werner J H Koopman, Evert M. van Schothorst, Clara D.M. van Karnebeek, Tom J.J. Schirris |
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| Přispěvatelé: | ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Paediatrics |
| Rok vydání: | 2022 |
| Předmět: |
Mitochondrial Diseases
mouse model Encephalopathy Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] Intervention Oxidative phosphorylation Mitochondrion Oxidative Phosphorylation Mouse model Mice Pathomechanism medicine Animals Humans Gene intervention Mice Knockout Electron Transport Complex I business.industry NDUFS4 Cancer Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] medicine.disease Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Leigh syndrome Pathophysiology Human and Animal Physiology Knockout mouse Cancer research WIAS Fysiologie van Mens en Dier Neurology (clinical) Leigh Disease business pathomechanism |
| Zdroj: | Brain, 145, 1, pp. 45-63 Brain, 145, 45-63 Brain, 145(1), 45-63 Brain, 145(1), 45-63. Oxford University Press Brain 145 (2022) 1 |
| ISSN: | 0006-8950 |
| Popis: | Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases. With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (complex I) induce isolated complex I deficiency and Leigh syndrome. This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA-encoded NDUFS4 gene, encoding the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) of complex I, induce 'mitochondrial complex I deficiency, nuclear type 1' (MC1DN1) and Leigh syndrome in paediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the Leigh syndrome pathomechanism and intervention testing. Here, we review and discuss the role of complex I and NDUFS4 mutations in human mitochondrial disease, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/Leigh syndrome pathomechanism and its therapeutic targeting. The NDUFS4 gene encodes an accessory subunit of OXPHOS complex I and its mutation causes mitochondrial disease in children. Van de Wal et al. review how Ndufs4 knockout mouse models have provided new insights into the disease pathomechanism and potential intervention strategies for these disorders. |
| Databáze: | OpenAIRE |
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