STARD7 maintains intestinal epithelial mitochondria architecture, barrier integrity, and protection from colitis
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 (ORCID: https://orcid.org/0000-0001-5303-5213)
- Sahiti Marella (ORCID: https://orcid.org/0000-0001-6937-6346)
- Ankit Sharma (ORCID: https://orcid.org/0000-0002-0156-1948)
- Mack B. Reynolds (ORCID: https://orcid.org/0000-0002-8445-3749)
- Senad Divanovic (ORCID: https://orcid.org/0000-0001-7538-0499)
- Arturo Raya‐Sandino (ORCID: https://orcid.org/0000-0001-7858-8017)
- Simon P. Hogan (ORCID: https://orcid.org/0000-0001-5793-4304)
- David Wu (ORCID: https://orcid.org/0000-0002-5621-0918)
- Sunil Tomar (ORCID: https://orcid.org/0000-0002-9258-399X)
- David N. O’Dwyer (ORCID: https://orcid.org/0000-0003-3214-380X)
- Rodolfo Ismael Cabrera-Silva
- Gila Idelman
- Lee A. Denson
- Lakshmi Narasimha Thota (ORCID: https://orcid.org/0000-0002-4523-210X)
- Srikanth Elesela (ORCID: https://orcid.org/0000-0002-6728-738X)
- Patricia Reichel
- Yael Haberman (ORCID: https://orcid.org/0000-0003-2680-1570)
- Asma Nusrat
- Mary O’Riordan (ORCID: https://orcid.org/0000-0001-6014-4637)
- Charles A. Parkos (ORCID: https://orcid.org/0000-0002-2490-7657)
- Varsha Ganesan
- Nicholas W. Lukacs (ORCID: https://orcid.org/0000-0003-2403-6481)
- Hock L. Tay (ORCID: https://orcid.org/0000-0002-7919-4308)
- Timothy E. Weaver
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Tel Aviv University (IL)
- University of Michigan (US)
- Sheba Medical Center (IL)
- Immune Tolerance Network (US)
- Institute of Experimental Endocrinology of the Slovak Academy of Sciences (SK)
- Michigan Medicine (US)
- Perinatal Institute (GB)
- University of Cincinnati (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1172/jci.insight.172978
- Citations
- 10
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- Cincinnati Children's Hospital Medical Center
- University of Michigan
- National Institutes of Health
- College of Pharmacy, University of Michigan
- NIH Office of the Director