COMP-prohibitin 2 interaction maintains mitochondrial homeostasis and controls smooth muscle cell identity

Yiting Jia,Qinghua Hu,Qingbo Xu,Chenfeng Mao,Rui Xiao,Changtao Jiang,Lemin Zheng,Fang Yu,Ming Zheng,Meili Wang,Wei Kong,Yingbao Wang,Yi Fu

doi:10.1038/s41419-018-0703-x

Abstract

Vascular smooth muscle cells (VSMCs) are highly phenotypically plastic, and loss of the contractile phenotype in VSMCs has been recognized at the early onset of the pathology of a variety of vascular diseases. However, the endogenous regulatory mechanism to maintain contractile phenotype in VSMCs remains elusive. Moreover, little has been known about the role of the mitochondrial bioenergetics in terms of VSMC homeostasis. Herein, we asked if glycoprotein COMP (Cartilage oligomeric matrix protein) is involved in mitochondrial bioenergetics and therefore regulates VSMCs homeostasis. By using fluorescence assay, subcellular western blot and liquid chromatography tandem mass spectrometry analysis, we found that extracellular matrix protein COMP unexpectedly localized within mitochondria. Further mitochondrial transplantation revealed that both mitochondrial and non-mitochondrial COMP maintained VSMC identity. Moreover, microarray analysis revealed that COMP deficiency impaired mitochondrial oxidative phosphorylation in VSMCs. Further study confirmed that COMP deficiency caused mitochondrial oxidative phosphorylation dysfunction accompanied by morphological abnormality. Moreover, the interactome of mitochondrial COMP revealed that COMP interacted with prohibitin 2, and COMP–prohibitin 2 interaction maintained mitochondrial homeostasis. Additionally, disruption of COMP–prohibitin 2 interaction caused VSMC dedifferentiation in vitro and enhanced the neointima formation post rat carotid artery injury in vivo. In conclusion, COMP–prohibitin 2 interaction in mitochondria plays an important role in maintaining the contractile phenotype of VSMCs by regulating mitochondrial oxidative phosphorylation. Maintaining the homeostasis of mitochondrial respiration through COMP–prohibitin 2 interaction may shed light on prevention of vascular disease.

Highlights

Vascular smooth muscle cells (VSMCs) are of high plasticity and can undergo reversible changes in phenotype in response to alterations in local environmental cues[1]
Cartilage oligomeric matrix protein (COMP) intracellularly localized in mitochondria We previously showed that the extracellular matrix (ECM) protein COMP is essential for maintaining the contractile phenotype of VSMCs, and siRNA-mediated silencing of COMP causes VSMC dedifferentiation[20]
Upon further investigation of submitochondrial localization, we found that COMP preferentially localized in the inner mitochondrial membrane (IMM)/matrix but was less abundant in the outer mitochondrial membrane (OMM)/intermembrane space (IMS) (Fig. 1c)

Summary

Introduction

Vascular smooth muscle cells (VSMCs) are of high plasticity and can undergo reversible changes in phenotype in response to alterations in local environmental cues[1]. Little has been known about the role of the bioenergetics of VSMC mitochondria in terms of vascular function and disease. The bioenergetics of human VSMCs via mitochondrial metabolism mainly relies on oxygen-consuming mitochondrial oxidative phosphorylation (OXPHOS) due to high efficiency of ATP production, whereas glycolysis is involved[12,13]. It has become increasingly evident that under certain disease conditions, there is damage to the mitochondria that limits their ability to generate ATP via oxidative phosphorylation, leading to mitochondrial dysfunction. A few studies have shown that during aortic VSMC dedifferentiation induced by serum or PDGF-BB, mitochondria undergo metabolic reprogramming and decreased ATP production[18]. The definitive role of mitochondrial respiration in the VSMC phenotypic transition and the underlying mechanism have been little studied

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Results

Conclusion