Chemical screening identifies ROCK as a target for recovering mitochondrial function in Hutchinson-Gilford progeria syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high-throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho-associated protein kinase (ROCK) inhibitor (Y-27632) as an effective agent. To elucidate the underlying mechanism of ROCK in regulating ROS levels, we performed a yeast two-hybrid screen and discovered that ROCK1 interacts with Rac1b. ROCK activation phosphorylated Rac1b at Ser71 and increased ROS levels by facilitating the interaction between Rac1b and cytochrome c. Conversely, ROCK inactivation with Y-27632 abolished their interaction, concomitant with ROS reduction. Additionally, ROCK activation resulted in mitochondrial dysfunction, whereas ROCK inactivation with Y-27632 induced the recovery of mitochondrial function. Furthermore, a reduction in the frequency of abnormal nuclear morphology and DNA double-strand breaks was observed along with decreased ROS levels. Thus, our study reveals a novel mechanism through which alleviation of the HGPS phenotype is mediated by the recovery of mitochondrial function upon ROCK inactivation.
Well Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon-si, Korea.
Hyun Tae
HT
Kang
Well Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon-si, Korea.
Joon Tae
JT
Park
Well Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon-si, Korea.
Kobong
K
Choi
Well Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon-si, Korea.
Hyo Jei Claudia
HJC
Choi
Well Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon-si, Korea.
Chul Won
CW
Jung
Well Aging Research Center, DGIST, Daegu, Korea.
Gyu Ree
GR
Kim
Well Aging Research Center, DGIST, Daegu, Korea.|Department of New Biology, DGIST, Daegu, Korea.
Young-Sam
YS
Lee
Well Aging Research Center, DGIST, Daegu, Korea.|Department of New Biology, DGIST, Daegu, Korea.
Sang Chul
SC
Park
D000577:Amides / Q000494:pharmacology*; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011371:Progeria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000577:Amides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; C108830:Y 27632; D045304:Cytochromes c; D054460:rho-Associated Kinases; D020830:rac1 GTP-Binding Protein

HGPS
; 
ROCK
; 
ROS
; Cytochrome c; Rac1b; Y-27632