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 Thota, Rodolfo Ismael 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 O’Riordan, Nicholas W. Lukacs, David N. O’Dwyer, Senad Divanovic, Asma Nusrat, Timothy E. Weaver, Simon P. Hogan
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.