STARD7 maintains intestinal epithelial mitochondria architecture, barrier integrity, and protection from colitis
Jazib Uddin, Ankit Sharma, David Wu, Sunil Tomar, Varsha Ganesan, Paula E. Reichel, Lakshmi Narasimha Rao Thota, Rodolfo I. Cabrera-Silva, Sahiti Marella, Gila Idelman, Hock L. Tay, Arturo Raya-Sandino, Mack B. Reynolds, Srikanth Elesela, Yael Haberman, Lee A. Denson, Charles A. Parkos, Mary X.D. O’Riordan, Nicholas W. Lukacs, David N. O’Dwyer, Senad Divanovic, Asma Nusrat, Timothy E. Weaver, Simon P. Hogan
Jazib Uddin, Ankit Sharma, David Wu, Sunil Tomar, Varsha Ganesan, Paula E. Reichel, Lakshmi Narasimha Rao Thota, Rodolfo I. Cabrera-Silva, Sahiti Marella, Gila Idelman, Hock L. Tay, Arturo Raya-Sandino, Mack B. Reynolds, Srikanth Elesela, Yael Haberman, Lee A. Denson, Charles A. Parkos, Mary X.D. O’Riordan, Nicholas W. Lukacs, David N. O’Dwyer, Senad Divanovic, Asma Nusrat, Timothy E. Weaver, Simon P. Hogan
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Research Article Inflammation

STARD7 maintains intestinal epithelial mitochondria architecture, barrier integrity, and protection from colitis

Abstract

Susceptibility to inflammatory bowel diseases (IBDs), Crohn’s disease (CD), and ulcerative colitis (UC) is linked with loss of intestinal epithelial barrier integrity and mitochondria dysfunction. Steroidogenic acute regulatory (StAR) protein-related lipid transfer (START) domain-containing protein 7 (STARD7) is a phosphatidylcholine-specific (PC-specific) lipid transfer protein that transports PC from the ER to the mitochondria, facilitating mitochondria membrane stabilization and respiration function. The aim of this study was to define the contribution of STARD7 in the regulation of the intestinal epithelial mitochondrial function and susceptibility to colitis. In silico analyses identified significantly reduced expression of STARD7 in patients with UC, which was associated with downregulation of metabolic function and a more severe disease phenotype. STARD7 was expressed in intestinal epithelial cells, and STARD7 knockdown resulted in deformed mitochondria and diminished aerobic respiration. Loss of mitochondria function was associated with reduced expression of tight junction proteins and loss of intestinal epithelial barrier integrity that could be recovered by AMPK activation. Stard7+/– mice were more susceptible to the development of DSS-induced and Il10–/– spontaneous models of colitis. STARD7 is critical for intestinal epithelial mitochondrial function and barrier integrity, and loss of STARD7 function increases susceptibility to IBD.

Authors

Jazib Uddin, Ankit Sharma, David Wu, Sunil Tomar, Varsha Ganesan, Paula E. Reichel, Lakshmi Narasimha Rao Thota, Rodolfo I. Cabrera-Silva, Sahiti Marella, Gila Idelman, Hock L. Tay, Arturo Raya-Sandino, Mack B. Reynolds, Srikanth Elesela, Yael Haberman, Lee A. Denson, Charles A. Parkos, Mary X.D. O’Riordan, Nicholas W. Lukacs, David N. O’Dwyer, Senad Divanovic, Asma Nusrat, Timothy E. Weaver, Simon P. Hogan

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Figure 3

STARD7 deficiency alters homeostatic intestinal epithelial barrier function.

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STARD7 deficiency alters homeostatic intestinal epithelial barrier funct...
Western blot of (A) STARD7 and (B) tight junction proteins in WT and Stard7+/– epithelial cells. (C) Densitometry analyses of tight junction proteins in WT and Stard7+/– epithelial cells (WT n = 6; Stard7+/– n = 6). (D) In vivo ileal epithelial permeability to FITC-dextran in WT and Stard7+/– mice (n = 6 WT; n = 8 Stard7+/– mice). (E) Representative photomicrograph (left) and quantification (right) of wound repair in primary epithelial monolayers from WT and Stard7+/– mice. Scale bars = 100 μm. Dashed line, edges of wounds. (F) Transepithelial electric resistance in Shhcre Stard7fl/fl epithelial cells (Shhcre n = 3; Shhcre Stard7fl/fl n = 3). (G) Time course of FITC-dextran flux in Shhcre Stard7fl/fl epithelial cells (Shhcre n = 3; Shhcre Stard7fl/fl n = 3). (H) Western blot of tight junction proteins in WT and Shhcre Stard7fl/fl epithelial cells. (I) Transepithelial electric resistance in Villincre Stard7fl/fl epithelial cells (WT n = 3; Villincre Stard7fl/fl n = 8). (J) Time course of FITC-dextran flux in Villincre Stard7fl/fl epithelial cells (WT n = 3; Villincre Stard7fl/fl n = 3). (K) Transepithelial electric resistance in WT, pLKO.1 shRNA–transduced and Stard7 shRNA–transduced CaCo-2BBe cell monolayers (WT n = 4; pLKO.1 n = 8; Stard7 n = 8). (L) Time course of FITC-dextran flux in WT and Stard7 shRNA–transduced CaCo-2BBe cell monolayers (WT n = 4; pLKO.1 n = 4; Stard7 n = 4). (M) Western blot of tight junction proteins in WT and Stard7 shRNA–transduced CaCo-2BBe cells. Data are representative of at least 2 independent experiments with at least 3 replicates per group. Each symbol in F, G, I, and K represents an individual well containing 500,000 cells. Data are presented as mean ± SEM. Statistical analysis performed using 1-way analysis of variance followed by Tukey’s multiple-comparison test or performed using an unpaired t test. *P <0.05, **P <0.01, ***P <0.001, ****P <0.0001.