Expression of Oxidative Phosphorylation Complexes and Mitochondrial Mass in Pediatric and Adult Inflammatory Bowel Disease

Abstract

Introduction. Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a multifactorial intestinal disorder but its precise etiology remains elusive. As the cells of the intestinal mucosa have high energy demands, mitochondria may play a role in IBD pathogenesis. The present study is aimed at evaluating the expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes in IBD. Material and Methods. 286 intestinal biopsy samples from the terminal ileum, ascending colon, and rectum from 124 probands (34 CD, 33 UC, and 57 controls) were stained immunohistochemically for all five OXPHOS complexes and the voltage-dependent anion-selective channel 1 protein (VDAC1 or porin). Expression levels were compared in multivariate models including disease stage (CD and UC compared to controls) and age (pediatric/adult). Results. Analysis of the terminal ileum of CD patients revealed a significant reduction of complex II compared to controls, and a trend to lower levels was evident for VDAC1 and the other OXPHOS complexes except complex III. A similar pattern was found in the rectum of UC patients: VDAC1, complex I, complex II, and complex IV were all significantly reduced, and complex III and V showed a trend to lower levels. Reductions were more prominent in older patients compared to pediatric patients and more marked in UC than CD. Conclusion. A reduced mitochondrial mass is present in UC and CD compared to controls. This is potentially a result of alterations of mitochondrial biogenesis or mitophagy. Reductions were more pronounced in older patients compared to pediatric patients, and more prominent in UC than CD. Complex I and II are more severely compromised than the other OXPHOS complexes. This has potential therapeutic implications, since treatments boosting biogenesis or influencing mitophagy could be beneficial for IBD treatment. Additionally, substances specifically stimulating complex I activity should be tested in IBD treatment.

Patient-derived Colonoids From Disease-spared Tissue Retain Inflammatory Bowel Disease-specific Transcriptomic Signatures

“…However, prior studies relied on transcriptomes from whole biopsies taken from actively inflamed tissue, 35 whereas, we focused on epithelium from locations that were inflammation-adjacent. Furthermore, the crypt orientation in immunohistological staining for OXPHOS complexes presented in other reports, 35 , 36 does not consistently offer insight into the crypt base. We utilized stem cell-biased culture conditions, which may have revealed transcriptional events that would remain unnoticed when examining the intestinal epithelium broadly.…”

Mitochondrial-related genes PDK2, CHDH, and ALDH5A1 served as a diagnostic signature and correlated with immune cell infiltration in ulcerative colitis

“…Choline dehydrogenase (CHDH) as the mitochondrial enzyme is responsible for catalyzing the dehydrogenation of choline into betaine aldehyde and regulates mitophagy by recruiting SQSTM1 and LC3 to the mitochondria [ 29 ]. In recent years, studies have shown the importance of mitophagy within the intestinal epithelium during UC pathogenesis [ 16 , 30 , 31 ]. CHDH also primarily contributes to biological processes such as inflammatory response, vascular lesion, metabolic process and cell cycle [ 32 ].…”

Hydrogen Sulfide Metabolizing Enzymes in the Intestinal Mucosa in Pediatric and Adult Inflammatory Bowel Disease

“…The samples were classified according to a previous study by Schneider et al [ 83 ]. Patients with macroscopically and histologically proven IBD were assigned to the study group.…”

“…If the results of the colonoscopy excluded UC and CD, they were appointed as controls. The analysis was conducted by the pathologists using a histologic severity score (HSS) in accordance with the study by Schneider et al [ 83 ]. Zero to three points were given in each of the categories of crypt architecture, signs of acute inflammation, signs of chronic inflammation and regeneration of the epithelium, resulting in a score range of 0–12.…”

“…After immunohistochemical staining, slides were scanned automatically at 20x magnification using the VS-120-L Olympus slide scanner 100-W system and processed using the Olympus VS-ASW-L100 program (Olympus, Shinjuku, Tokyo, Japan). The staining was evaluated in accordance with a previous study by Schneider et al [ 83 ]. First, the staining intensity of IEC was assessed using a score system ranging from 0 to 3 (0 = no staining, 1 = weak staining, 2 = moderate staining, 3 = strong staining) ( Figure 2 ).…”