ATF7–PINK1 Axis Governs Mitophagy and Intestinal Inflammation in Ulcerative Colitis

Abstract

Ulcerative colitis (UC), a chronic inflammatory bowel disease, is marked by sustained inflammation and excessive apoptosis of intestinal epithelial cells (IECs). Despite progress in understanding UC pathogenesis, the role of activating transcription factors (ATFs) in disease progression remains elusive. Here, we profile the expression of ATF family members (ATF1–ATF7) in the colonic mucosa of UC patients and identify ATF7 as a critical regulator of mitophagy through its control of PTEN-induced kinase 1 (PINK1). Expression levels of ATF1–ATF7 were quantified in colonic mucosal samples from UC patients (n = 219) and healthy controls (n = 105) via quantitative PCR. Using IEC-specific ATF7 knockout mouse models and human CCD 841 CoN colonic epithelial cells, we employed ChIP-seq, dual-luciferase assays, transmission electron microscopy, and immunofluorescence to elucidate their roles in mitophagy and disease progression. Clinical correlation between ATF7 expression and disease severity was assessed using the Mayo score. ATF7 expression was significantly reduced in UC patients and inversely correlated with disease severity. Mechanistically, ATF7 was identified as a direct transcriptional activator of PINK1, a key mitophagy regulator. Loss of ATF7 or PINK1 disrupted mitophagy, exacerbating mitochondrial dysfunction, IEC apoptosis, and colonic inflammation in vivo and in vitro. Our findings uncover a pivotal ATF7-PINK1 axis that governs mitophagy and limits UC progression. The inverse correlation between ATF7 expression and UC severity highlights its potential as a therapeutic target, offering new avenues for intervention in this debilitating disease.