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

Biochim Biophys Acta Mol Basis Dis. 2020 Jun 1;1866(6):165727. doi: 10.1016/j.bbadis.2020.165727. Epub 2020 Feb 15.


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.

Keywords: Clofibrate; Hepatotoxicity; KH176; Mitochondrial complex I deficiency; Peroxisome proliferator activated receptor (PPAR); Redox modulator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Bezafibrate / pharmacology
  • Chromans / pharmacology*
  • Clofibrate / pharmacology*
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism
  • Fatty Acids / metabolism
  • Humans
  • Leigh Disease / drug therapy
  • Leigh Disease / metabolism
  • Leigh Disease / pathology
  • Longevity / drug effects*
  • Mice
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondrial Diseases / drug therapy*
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Motor Activity / drug effects
  • Oxidation-Reduction / drug effects
  • Peroxisome Proliferator-Activated Receptors / agonists
  • Peroxisome Proliferator-Activated Receptors / genetics


  • Chromans
  • Fatty Acids
  • Ndufs4 protein, mouse
  • Peroxisome Proliferator-Activated Receptors
  • Adenosine Triphosphate
  • Electron Transport Complex I
  • Clofibrate
  • 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
  • Bezafibrate

Supplementary concepts

  • Mitochondrial complex I deficiency