Metabolic regulation of the proteasome under hypoxia by Poldip2 controls fibrotic signaling in vascular smooth muscle cells

• Published in: Free radical biology & medicine Vol. 195; pp. 283 - 297
• Main Authors: Paredes, Felipe, Williams, Holly C., Suster, Izabela, Tejos, Macarena, Fuentealba, Roberto, Bogan, Bethany, Holden, Claire M., San Martin, Alejandra
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2023
• Subjects: CCN2; Cell cycle; Connective Tissue Growth Factor - genetics; Connective Tissue Growth Factor - metabolism; Humans; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Mitochondria; Muscle, Smooth, Vascular - metabolism; Nuclear Proteins - metabolism; Poldip2; Proteasome; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Signal Transduction; GFPT2; SRF; Poldip2; HK2; CCNA2; Mitochondria; PSMC1; Cell cycle; CDK2; Hypoxia; CCN2; OGT; Proteasome; EZH2
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2022.12.098

The polymerase delta interacting protein 2 (Poldip2) is a nuclear-encoded mitochondrial protein required for oxidative metabolism. Under hypoxia, Poldip2 expression is repressed by an unknown mechanism. Therefore, low levels of Poldip2 are required to maintain glycolytic metabolism. The Cellular Communication Network Factor 2 (CCN2, Connective tissue growth factor, CTGF) is a profibrogenic molecule highly expressed in cancer and vascular inflammation in advanced atherosclerosis. Because CCN2 is upregulated under hypoxia and is associated with glycolytic metabolism, we hypothesize that Poldip2 downregulation is responsible for the upregulation of profibrotic signaling under hypoxia. Here, we report that Poldip2 is repressed under hypoxia by a mechanism that requires the activation of the enhancer of zeste homolog 2 repressive complex (EZH2) downstream from the Cyclin-Dependent Kinase 2 (CDK2). Importantly, we found that Poldip2 repression is required for CCN2 expression downstream of metabolic inhibition of the ubiquitin-proteasome system (UPS)-dependent stabilization of the serum response factor. Pharmacological or gene expression inhibition of CDK2 under hypoxia reverses Poldip2 downregulation, the inhibition of the UPS, and the expression of CCN2, collagen, and fibronectin. Thus, our findings connect cell cycle regulation and proteasome activity to mitochondrial function and fibrotic responses under hypoxia. [Display omitted] •In hypoxia, Poldip2 is repressed by EZH2-mediated signaling downstream of the cell cycle.•Poldip2 expression under hypoxia controls the activity of the Ubiquitin proteasome system.•Cell cycle regulation controls pro-fibrotic signaling under hypoxia.•Poldip2 deficiency exacerbates hypoxia-induced vascular hypoxia.