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Published on: September 27, 2019

In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis

Carlo Viscomi1, Emanuela Bottani, Gabriele Civiletto

  • 1Unit of Molecular Neurogenetics, The Foundation Carlo Besta Institute of Neurology-IRCCS, Milan, Italy.

Cell Metabolism
|July 5, 2011
PubMed

Insights

Activating AMP-activated protein kinase (AMPK) partially corrected cytochrome c-oxidase (COX) deficiency in mouse models of mitochondrial disease. This approach also significantly improved motor function in one model, suggesting therapeutic potential.

Area of Science:

  • Mitochondrial biology
  • Molecular medicine
  • Genetics and genomics

Background:

  • Mitochondrial diseases are often characterized by defects in the electron transport chain, such as reduced cytochrome c-oxidase (COX) activity.
  • Mitochondrial biogenesis, regulated by pathways involving PPAR and AMPK/PGC-1α, is a proposed therapeutic strategy for these disorders.
  • Recombinant mouse models with specific genetic defects (Surf1, Sco2, Cox15) provide tools to investigate therapeutic interventions.

Purpose of the Study:

  • To test the hypothesis that activating PPAR or AMPK/PGC-1α pathways can treat mitochondrial disease.
  • To evaluate the efficacy of PGC-1α overexpression and pharmacological agonists (bezafibrate, AICAR) in mouse models of COX deficiency.

Main Methods:

  • Utilized three mouse models with genetic defects in COX activity: Surf1 knockout (KO), Sco2 knockout/knockin (KO/KI), and muscle-restricted Cox15 KO.
  • Overexpressed PGC-1α in skeletal muscle of Surf1 KO mice.
  • Administered bezafibrate (pan-PPAR agonist) and AICAR (AMPK agonist) to affected mouse models.

Main Results:

  • PGC-1α overexpression in Surf1 KO mice induced mitochondrial biogenesis and partially restored COX activity.
  • Bezafibrate treatment showed no beneficial effect and caused adverse effects in Surf1 and Cox15 KO models.
  • AICAR treatment partially corrected COX deficiency across all three models and significantly improved motor function in Sco2(KO/KI) mice.

Conclusions:

  • Activating AMPK via AICAR shows promise for treating mitochondrial diseases characterized by COX deficiency.
  • Pharmacological activation of AMPK offers a potential therapeutic avenue, particularly for improving motor deficits.
  • PPAR activation is not a viable therapeutic strategy for these specific COX-deficient mitochondrial disease models.

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