Frambach 2020 Biochim Biophys Acta Mol Basis Dis

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Frambach SJCM, van de Wal MAE, van den Broek PHH, Smeitink JAM, Russel FGM, de Haas R, Schirris TJJ (2020) Effects of clofibrate and KH176 on life span and motor function in mitochondrial complex I-deficient mice. Biochim Biophys Acta Mol Basis Dis 1866:165727.

» PMID: 32070771 Open Access

Frambach SJCM, van de Wal MAE, van den Broek PHH, Smeitink JAM, Russel FGM, de Haas R, Schirris TJJ (2020) Biochim Biophys Acta Mol Basis Dis

Abstract: Mitochondrial complex I (CI), the first multiprotein enzyme complex of the OXPHOS system, executes a major role in cellular ATP generation. Consequently, dysfunction of this complex has been linked to inherited metabolic disorders, including Leigh disease (LD), an often fatal disease in early life. Development of clinical effective treatments for LD remains challenging due to the complex pathophysiological nature. Treatment with the peroxisome proliferation-activated receptor (PPAR) agonist bezafibrate improved disease phenotype in several mitochondrial disease mouse models mediated via enhanced mitochondrial biogenesis and fatty acid β-oxidation. However, the therapeutic potential of this mixed PPAR (α, δ/β, γ) agonist is severely hampered by hepatotoxicity, which is possibly caused by activation of PPARγ. Here, we aimed to investigate the effects of the PPARα-specific fibrate clofibrate in mitochondrial CI-deficient (Ndufs4-/-) mice. Clofibrate increased lifespan and motor function of Ndufs4-/- mice, while only marginal hepatotoxic effects were observed. Due to the complex clinical and cellular phenotype of CI-deficiency, we also aimed to investigate the therapeutic potential of clofibrate combined with the redox modulator KH176. As described previously, single treatment with KH176 was beneficial, however, combining clofibrate with KH176 did not result in an additive effect on disease phenotype in Ndufs4-/- mice. Overall, both drugs have promising, but independent and nonadditive, properties for the pharmacological treatment of CI-deficiency-related mitochondrial diseases.

Copyright © 2020. Published by Elsevier B.V.

Keywords: Clofibrate, Hepatotoxicity, KH176, Mitochondrial complex I deficiency, Peroxisome proliferator activated receptor (PPAR), Redox modulator Bioblast editor: Plangger M O2k-Network Lab: NL Nijmegen Koopman WJH


Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology 

Stress:Mitochondrial disease  Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue  Enzyme: Complex I 

Coupling state: LEAK, OXPHOS  Pathway: F, N, S, Gp, CIV, Other combinations, ROX  HRR: Oxygraph-2k 

Labels, 2020-02