Li Wang1, Tianzheng Yu1, Hakjoo Lee1, Dawn K O'Brien1, Hiromi Sesaki2, Yisang Yoon3. 1. Department of Physiology, Medical College of Georgia, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA 30912-3000, USA. 2. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 3. Department of Physiology, Medical College of Georgia, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA 30912-3000, USA yyoon@gru.edu.
Abstract
AIMS: Vascular smooth muscle cell (VSMC) migration in response to arterial wall injury is a critical process in the development of intimal hyperplasia. Cell migration is an energy-demanding process that is predicted to require mitochondrial function. Mitochondria are morphologically dynamic, undergoing continuous shape change through fission and fusion. However, the role of mitochondrial morphology in VSMC migration is not well understood. The aim of the study is to understand how mitochondrial fission contributes to VSMC migration and provides its in vivo relevance in the mouse model of intimal hyperplasia. METHODS AND RESULTS: In primary mouse VSMCs, the chemoattractant PDGF induced mitochondrial shortening through the mitochondrial fission protein dynamin-like protein 1 (DLP1)/Drp1. Perturbation of mitochondrial fission by expressing the dominant-negative mutant DLP1-K38A or by DLP1 silencing greatly decreased PDGF-induced lamellipodia formation and VSMC migration, indicating that mitochondrial fission is an important process in VSMC migration. PDGF induced an augmentation of mitochondrial energetics as well as ROS production, both of which were found to be necessary for VSMC migration. Mechanistically, the inhibition of mitochondrial fission induced an increase of mitochondrial inner membrane proton leak in VSMCs, abrogating the PDGF-induced energetic enhancement and an ROS increase. In an in vivo model of intimal hyperplasia, transgenic mice expressing DLP1-K38A displayed markedly reduced ROS levels and neointima formation in response to femoral artery wire injury. CONCLUSIONS: Mitochondrial fission is an integral process in cell migration, and controlling mitochondrial fission can limit VSMC migration and the pathological intimal hyperplasia by altering mitochondrial energetics and ROS levels. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Vascular smooth muscle cell (VSMC) migration in response to arterial wall injury is a critical process in the development of intimal hyperplasia. Cell migration is an energy-demanding process that is predicted to require mitochondrial function. Mitochondria are morphologically dynamic, undergoing continuous shape change through fission and fusion. However, the role of mitochondrial morphology in VSMC migration is not well understood. The aim of the study is to understand how mitochondrial fission contributes to VSMC migration and provides its in vivo relevance in the mouse model of intimal hyperplasia. METHODS AND RESULTS: In primary mouseVSMCs, the chemoattractant PDGF induced mitochondrial shortening through the mitochondrial fission protein dynamin-like protein 1 (DLP1)/Drp1. Perturbation of mitochondrial fission by expressing the dominant-negative mutant DLP1-K38A or by DLP1 silencing greatly decreased PDGF-induced lamellipodia formation and VSMC migration, indicating that mitochondrial fission is an important process in VSMC migration. PDGF induced an augmentation of mitochondrial energetics as well as ROS production, both of which were found to be necessary for VSMC migration. Mechanistically, the inhibition of mitochondrial fission induced an increase of mitochondrial inner membrane proton leak in VSMCs, abrogating the PDGF-induced energetic enhancement and an ROS increase. In an in vivo model of intimal hyperplasia, transgenic mice expressing DLP1-K38A displayed markedly reduced ROS levels and neointima formation in response to femoral artery wire injury. CONCLUSIONS: Mitochondrial fission is an integral process in cell migration, and controlling mitochondrial fission can limit VSMC migration and the pathological intimal hyperplasia by altering mitochondrial energetics and ROS levels. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Camila Lopez-Crisosto; Christian Pennanen; Cesar Vasquez-Trincado; Pablo E Morales; Roberto Bravo-Sagua; Andrew F G Quest; Mario Chiong; Sergio Lavandero Journal: Nat Rev Cardiol Date: 2017-03-09 Impact factor: 32.419
Authors: Huiliang Zhang; Pei Wang; Sara Bisetto; Yisang Yoon; Quan Chen; Shey-Shing Sheu; Wang Wang Journal: Cardiovasc Res Date: 2016-10-29 Impact factor: 10.787
Authors: Dimitra Pouli; Mihaela Balu; Carlo A Alonzo; Zhiyi Liu; Kyle P Quinn; Francisca Rius-Diaz; Ronald M Harris; Kristen M Kelly; Bruce J Tromberg; Irene Georgakoudi Journal: Sci Transl Med Date: 2016-11-30 Impact factor: 17.956
Authors: Jiali Cheng; Gayani Nanayakkara; Ying Shao; Ramon Cueto; Luqiao Wang; William Y Yang; Ye Tian; Hong Wang; Xiaofeng Yang Journal: Adv Exp Med Biol Date: 2017 Impact factor: 2.622