Perturbed Mitochondrial Dynamics Is a Novel Feature of Colitis That Can Be Targeted to Lessen Disease.
Cell Mol Gastroenterol Hepatol
; 10(2): 287-307, 2020.
Article
in En
| MEDLINE
| ID: mdl-32298841
ABSTRACT
BACKGROUND & AIMS:
Mitochondria exist in a constantly remodelling network, and excessive fragmentation can be pathophysiological. Mitochondrial dysfunction can accompany enteric inflammation, but any contribution of altered mitochondrial dynamics (ie, fission/fusion) to gut inflammation is unknown. We hypothesized that perturbed mitochondrial dynamics would contribute to colitis.METHODS:
Quantitative polymerase chain reaction for markers of mitochondrial fission and fusion was applied to tissue from dextran sodium sulfate (DSS)-treated mice. An inhibitor of mitochondrial fission, P110 (prevents dynamin related protein [Drp]-1 binding to mitochondrial fission 1 protein [Fis1]) was tested in the DSS and di-nitrobenzene sulfonic acid (DNBS) models of murine colitis, and the impact of DSS ± P110 on intestinal epithelial and macrophage mitochondria was assessed in vitro.RESULTS:
Analysis of colonic tissue from mice with DSS-colitis revealed increased mRNA for molecules associated with mitochondrial fission (ie, Drp1, Fis1) and fusion (optic atrophy factor 1) and increased phospho-Drp1 compared with control. Systemic delivery of P110 in prophylactic or treatment regimens reduced the severity of DSS- or DNBS-colitis and the subsequent hyperalgesia in DNBS-mice. Application of DSS to epithelial cells or macrophages caused mitochondrial fragmentation. DSS-evoked perturbation of epithelial cell energetics and mitochondrial fragmentation, but not cell death, were ameliorated by in vitro co-treatment with P110.CONCLUSIONS:
We speculate that the anti-colitic effect of systemic delivery of the anti-fission drug, P110, works at least partially by maintaining enterocyte and macrophage mitochondrial networks. Perturbed mitochondrial dynamics can be a feature of intestinal inflammation, the suppression of which is a potential novel therapeutic direction in inflammatory bowel disease.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptide Fragments
/
Colitis, Ulcerative
/
Colon
/
Mitochondrial Dynamics
/
GTP Phosphohydrolases
/
Intestinal Mucosa
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Cell Mol Gastroenterol Hepatol
Year:
2020
Document type:
Article