Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention.

Brain : a journal of neurology 2022 Mar 29

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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 Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

Citation

Melissa A E van de Wal, Merel J W Adjobo-Hermans, Jaap Keijer, Tom J J Schirris, Judith R Homberg, Mariusz R Wieckowski, Sander Grefte, Evert M van Schothorst, Clara van Karnebeek, Albert Quintana, Werner J H Koopman. Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention. Brain : a journal of neurology. 2022 Mar 29;145(1):45-63