Screening for active small molecules in mitochondrial complex I deficient patient's fibroblasts, reveals AICAR as the most beneficial compound

PLoS One. 2011;6(10):e26883. doi: 10.1371/journal.pone.0026883. Epub 2011 Oct 26.


Congenital deficiency of the mitochondrial respiratory chain complex I (CI) is a common defect of oxidative phosphorylation (OXPHOS). Despite major advances in the biochemical and molecular diagnostics and the deciphering of CI structure, function assembly and pathomechanism, there is currently no satisfactory cure for patients with mitochondrial complex I defects. Small molecules provide one feasible therapeutic option, however their use has not been systematically evaluated using a standardized experimental system. In order to evaluate potentially therapeutic compounds, we set up a relatively simple system measuring different parameters using only a small amount of patient's fibroblasts, in glucose free medium, where growth is highly OXPOS dependent. Ten different compounds were screened using fibroblasts derived from seven CI patients, harboring different mutations.5-Aminoimidazole-4-carboxamide ribotide (AICAR) was found to be the most beneficial compound improving growth and ATP content while decreasing ROS production. AICAR also increased mitochondrial biogenesis without altering mitochondrial membrane potential (Δψ). Fluorescence microscopy data supported increased mitochondrial biogenesis and activation of the AMP activated protein kinase (AMPK). Other compounds such as; bezafibrate and oltipraz were rated as favorable while polyphenolic phytochemicals (resverastrol, grape seed extract, genistein and epigallocatechin gallate) were found not significant or detrimental. Although the results have to be verified by more thorough investigation of additional OXPHOS parameters, preliminary rapid screening of potential therapeutic compounds in individual patient's fibroblasts could direct and advance personalized medical treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Aminoimidazole Carboxamide / therapeutic use
  • Cell Proliferation
  • Cells, Cultured
  • Drug Discovery / methods
  • Drug Evaluation, Preclinical / methods*
  • Electron Transport Complex I / deficiency
  • Electron Transport Complex I / drug effects
  • Fibroblasts / drug effects*
  • Fibroblasts / pathology
  • Humans
  • Membrane Potential, Mitochondrial
  • Mitochondrial Diseases / pathology
  • Oxidative Phosphorylation / drug effects
  • Reactive Oxygen Species
  • Ribonucleotides / pharmacology*
  • Ribonucleotides / therapeutic use


  • Reactive Oxygen Species
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Adenosine Triphosphate
  • Electron Transport Complex I
  • AICA ribonucleotide

Supplementary concepts

  • Mitochondrial complex I deficiency