Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen secretion
Ritu Bansal, Monica Torres, Matthew Hunt, Nuoqi Wang, Margarita Chatzopoulou, Mansi Manchanda, Evan P. Taddeo, Cynthia Shu, Orian S. Shirihai, Etty Bachar-Wikstrom, Jakob D. Wikstrom
Ritu Bansal, Monica Torres, Matthew Hunt, Nuoqi Wang, Margarita Chatzopoulou, Mansi Manchanda, Evan P. Taddeo, Cynthia Shu, Orian S. Shirihai, Etty Bachar-Wikstrom, Jakob D. Wikstrom
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Research Article Dermatology

Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen secretion

Abstract

Central for wound healing is the formation of granulation tissue, which largely consists of collagen and whose importance stretches past wound healing, including being implicated in both fibrosis and skin aging. Cyclophilin D (CyD) is a mitochondrial protein that regulates the permeability transition pore, known for its role in apoptosis and ischemia-reperfusion. To date, the role of CyD in human wound healing and collagen generation has been largely unexplored. Here, we show that CyD was upregulated in normal wounds and venous ulcers, likely adaptive as CyD inhibition impaired reepithelialization, granulation tissue formation, and wound closure in both human and pig models. Overexpression of CyD increased keratinocyte migration and fibroblast proliferation, while its inhibition reduced migration. Independent of wound healing, CyD inhibition in fibroblasts reduced collagen secretion and caused endoplasmic reticulum collagen accumulation, while its overexpression increased collagen secretion. This was confirmed in a Ppif-KO mouse model, which showed a reduction in skin collagen. Overall, this study revealed previously unreported roles of CyD in skin, with implications for wound healing and beyond.

Authors

Ritu Bansal, Monica Torres, Matthew Hunt, Nuoqi Wang, Margarita Chatzopoulou, Mansi Manchanda, Evan P. Taddeo, Cynthia Shu, Orian S. Shirihai, Etty Bachar-Wikstrom, Jakob D. Wikstrom

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Figure 1

Cyclophilin D is upregulated in normal wound healing as well as in chronic venous leg ulcers in the elderly.

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Cyclophilin D is upregulated in normal wound healing as well as in chron...
(A) Summary of experimental procedures. (B) NanoString profiling showing expression of apoptosis, necrosis, and permeability transition pore-associated genes, including PPIF and its interactors. Heatmap illustrates alterations in gene expression with fold change > 1.5 (green, increased expression; red, reduced expression). n = 7 (day 0/1/7); 12 (CW). (C) Publicly available RNA-Seq gene expression analysis of PPIF in intact skin, wound, and CW biopsies. (D and E) Representative images and quantification (mean ± SEM) of PPIF RNA expression in wound healing days 0, 1, and 7 after in situ hybridization staining. PPIF RNA puncti are visible as pink dots. Scale bar: 100 μm (full size); 50 μm (zoom). n = 5. (F) Representative fluorescence images of day 0, 1, and 7 skin biopsies demonstrating the assessment of PPIF expression in human wound healing. The white lines depict the demarcation of the epidermis, dermis, and wound bed. Scale bar: 100 μm (full size); 50 μm (zoom). n = 5. (G) Quantification (mean ± SEM) of PPIF fluorescence intensity in the epidermis and dermis after normalization to day 0. (H and I) Immunoblot and quantification (mean ± SEM) showing CyD protein expression in human wound samples. n = 4. **P < 0.01; *P < 0.05; 2-way ANOVA.