Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells.
Several lines of evidence suggest that mitochondrial dysfunction plays a critical role in the pathogenesis of microvascular complications of diabetes, including diabetic nephropathy. However, the signaling pathways by which hyperglycemia leads to mitochondrial dysfunction are not fully understood. Here we examined the role of Rho-associated coiled coil-containing protein kinase 1 (ROCK1) on mitochondrial dynamics by generating two diabetic mouse models with targeted deletions of ROCK1 and an inducible podocyte-specific knockin mouse expressing a constitutively active (cA) mutant of ROCK1. Our findings suggest that ROCK1 mediates hyperglycemia-induced mitochondrial fission by promoting dynamin-related protein-1 (Drp1) recruitment to the mitochondria. Deletion of ROCK1 in diabetic mice prevented mitochondrial fission, whereas podocyte-specific cA-ROCK1 mice exhibited increased mitochondrial fission. Importantly, we found that ROCK1 triggers mitochondrial fission by phosphorylating Drp1 at serine 600 residue. These findings provide insights into the unexpected role of ROCK1 in a signaling cascade that regulates mitochondrial dynamics.
Department of Medicine, Nephrology, Baylor College of Medicine, Houston, TX 77030, USA.
Wenjian
W
Wang
Yin
Y
Wang
Jianyin
J
Long
Jinrong
J
Wang
Sandra B
SB
Haudek
Paul
P
Overbeek
Benny H J
BH
Chang
Paul T
PT
Schumacker
Farhad R
FR
Danesh
D000595:Amino Acid Sequence; D000704:Analysis of Variance; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005434:Flow Cytometry; D017353:Gene Deletion; D055879:Gene Knock-In Techniques; D050533:Glomerular Basement Membrane / Q000473:pathology; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000209:etiology / Q000378:metabolism*; D023421:Models, Animal; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010766:Phosphorylation; D050199:Podocytes / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016415:Sequence Alignment; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D034741:RNA, Small Interfering; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; C486391:Dnm1l protein, mouse; D034281:Dynamins