screening for active small molecules in mitochondrial complex i deficient patients fibroblasts, reveals aicar as the most beneficial compound筛选线粒体的活性小分子复杂的我缺乏患者的成纤维细胞,揭示爱卡是最有益的化合物.pdfVIP

Screening for Active Small Molecules in Mitochondrial Complex I Deficient Patient’s Fibroblasts, Reveals AICAR as the Most Beneficial Compound 1. 1. 1 1 2 1 Anna Golubitzky , Phyllis Dan , Sarah Weissman , Gabriela Link , Jakob D. Wikstrom , Ann Saada * 1 Monique and Jacques Roboh Department of Genetic Research, Department of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, Israel, 2 Department of Endocrinology and Metabolism, Hadassah, Hebrew University Medical Center, Jerusalem, Israel Abstract 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 mitochondria