OBJECTIVE: Mitochondrial production of oxidants contributes to a variety of pathological conditions including the vascular complications of diabetes, neurodegenerative diseases, and cellular senescence. We postulated that a transcriptional coactivator, peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha), a major regulator of oxidative metabolism and mitochondrial biogenesis, could be involved in the transcriptional regulation of the mitochondrial antioxidant defense system in vascular endothelial cells. METHODS AND RESULTS: We show that PGC-1alpha is present in human, bovine, and mouse endothelial cells and positively modulates the expression of the mitochondrial detoxification system. Endothelial cells that overexpress PGC-1alpha show reduced accumulation of reactive oxygen species (ROS), increased mitochondrial membrane potential, and reduced apoptotic cell death both in basal and oxidative stress conditions. Downregulation of PGC-1alpha levels by siRNA reduces the expression of mitochondrial detoxification proteins. CONCLUSIONS: These results unveil a novel regulatory pathway that links mitochondrial activity and mitochondrial oxidative stress protective systems. In addition, they suggest that PGC-1alpha could play a crucial protective role in vascular complications of diabetes, where the mitochondrial metabolism of glucose has been shown to result in oxidative stress and vascular endothelial cell dysfunction.
OBJECTIVE: Mitochondrial production of oxidants contributes to a variety of pathological conditions including the vascular complications of diabetes, neurodegenerative diseases, and cellular senescence. We postulated that a transcriptional coactivator, peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha), a major regulator of oxidative metabolism and mitochondrial biogenesis, could be involved in the transcriptional regulation of the mitochondrial antioxidant defense system in vascular endothelial cells. METHODS AND RESULTS: We show that PGC-1alpha is present in human, bovine, and mouse endothelial cells and positively modulates the expression of the mitochondrial detoxification system. Endothelial cells that overexpress PGC-1alpha show reduced accumulation of reactive oxygen species (ROS), increased mitochondrial membrane potential, and reduced apoptotic cell death both in basal and oxidative stress conditions. Downregulation of PGC-1alpha levels by siRNA reduces the expression of mitochondrial detoxification proteins. CONCLUSIONS: These results unveil a novel regulatory pathway that links mitochondrial activity and mitochondrial oxidative stress protective systems. In addition, they suggest that PGC-1alpha could play a crucial protective role in vascular complications of diabetes, where the mitochondrial metabolism of glucose has been shown to result in oxidative stress and vascular endothelial cell dysfunction.
Authors: Song-Young Park; Matthew J Rossman; Jayson R Gifford; Leena P Bharath; Johann Bauersachs; Russell S Richardson; E Dale Abel; J David Symons; Christian Riehle Journal: Am J Physiol Heart Circ Physiol Date: 2016-01-29 Impact factor: 4.733
Authors: Thomas K Felder; Selma M Soyal; Hannes Oberkofler; Penelope Hahne; Simon Auer; Richard Weiss; Gabriele Gadermaier; Karl Miller; Franz Krempler; Harald Esterbauer; Wolfgang Patsch Journal: J Biol Chem Date: 2011-10-18 Impact factor: 5.157
Authors: Rafael O Fernandes; Jéssica H P Bonetto; Boran Baregzay; Alexandre L de Castro; Stephanie Puukila; Heidi Forsyth; Paulo C Schenkel; Susana F Llesuy; Ilma Simoni Brum; Alex Sander R Araujo; Neelam Khaper; Adriane Belló-Klein Journal: Mol Cell Biochem Date: 2014-12-07 Impact factor: 3.396