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

Autor: Melissa A.E. van de Wal, Sanne J. C. M. Frambach, Frans G. M. Russel, Jan A.M. Smeitink, Tom J.J. Schirris, Ria de Haas, Petra H.H. van den Broek
Rok vydání: 2020
Předmět:
0301 basic medicine
Agonist
Enzyme complex
Mitochondrial Diseases
medicine.drug_class
Mitochondrial disease
Longevity
Peroxisome Proliferator-Activated Receptors
Vascular damage Radboud Institute for Health Sciences [Radboudumc 16]
Peroxisome proliferator-activated receptor
Fibrate
Motor Activity
Pharmacology
Mice
03 medical and health sciences
Adenosine Triphosphate
0302 clinical medicine
All institutes and research themes of the Radboud University Medical Center
medicine
Animals
Humans
Clofibrate
Chromans
Molecular Biology
Mice
Knockout
chemistry.chemical_classification
Electron Transport Complex I
Bezafibrate
Fatty Acids
Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]
medicine.disease
Mitochondria
030104 developmental biology
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]
chemistry
Mitochondrial biogenesis
Molecular Medicine
Leigh Disease
Oxidation-Reduction
030217 neurology & neurosurgery
medicine.drug
Zdroj: Biochimica et Biophysica Acta. Molecular Basis of Disease, 1866
Biochimica et Biophysica Acta. Molecular Basis of Disease, 1866, 6
ISSN: 0925-4439
Popis: 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.
Databáze: OpenAIRE
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