Effects of clofibrate and KH176 on life span and motor function in mitochondrial complex I-deficient mice

Publication date: Available online 15 February 2020Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Sanne J.C.M. Frambach, Melissa A.E. van de Wal, Petra H.H. van den Broek, Jan A.M. Smeitink, Frans G.M. Russel, Ria de Haas, Tom J.J. SchirrisAbstractMitochondrial 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 c...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research