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Sci Rep. 2014 Jun 13;4:5285. doi: 10.1038/srep05285.

A method to identify and validate mitochondrial modulators using mammalian cells and the worm C. elegans.

Author information

  • 11] Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland [2].
  • 2Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
  • 31] Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland [2] Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

Mitochondria are semi-autonomous organelles regulated by a complex network of proteins that are vital for many cellular functions. Because mitochondrial modulators can impact many aspects of cellular homeostasis, their identification and validation has proven challenging. It requires the measurement of multiple parameters in parallel to understand the exact nature of the changes induced by such compounds. We developed a platform of assays scoring for mitochondrial function in two complementary models systems, mammalian cells and C. elegans. We first optimized cell culture conditions and established the mitochondrial signature of 1,200 FDA-approved drugs in liver cells. Using cell-based and C. elegans assays, we further defined the metabolic effects of two pharmacological classes that emerged from our hit list, i.e. imidazoles and statins. We found that these two drug classes affect respiration through different and cholesterol-independent mechanisms in both models. Our screening strategy enabled us to unequivocally identify compounds that have toxic or beneficial effects on mitochondrial activity. Furthermore, the cross-species approach provided novel mechanistic insight and allowed early validation of hits that act on mitochondrial function.

PMID:
24923838
[PubMed - in process]
PMCID:
PMC4055904
Free PMC Article
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