TGF-β1 Directs TFAM-Mediated Mitochondrial Reprogramming in Oral Submucous Fibrosis

Area of Science:

• Cell Biology
• Mitochondrial Bioenergetics
• Fibrosis Research

Background:

• Oral submucous fibrosis (OSMF) involves persistent, overactive fibroblasts with altered metabolism and cytoskeletal changes.
• Arecoline and transforming growth factor-beta (TGF-β) are key mediators implicated in OSMF pathogenesis.
• Understanding fibroblast behavior and mitochondrial dynamics is crucial for developing effective OSMF treatments.

Purpose of the Study:

• To evaluate the effects of arecoline and TGF-β on mitochondrial bioenergetics and the phenotype of oral fibroblasts.
• To investigate the role of mitochondrial fission and fusion in arecoline- and TGF-β-induced fibroblast responses.
• To correlate in vitro findings with clinical observations in human OSMF tissue samples.

Main Methods:

• Human oral fibroblasts were treated with arecoline, TGF-β1, and combinations.
• Cell survival, mitochondrial fusion/fission (OPA-1, MFN-2, DRP-1), and metabolic profiles (TFAM, hexokinase II) were assessed.
• Real-time PCR, immunofluorescence, Seahorse analysis, and analysis of archival OSMF patient biopsies were employed.

Main Results:

• Arecoline induced significant oral fibroblast cell death, which was rescued by TGF-β1.
• Arecoline promoted mitochondrial fission and a glycolytic metabolic profile, while TGF-β1 induced mitochondrial fusion.
• Combined treatments improved cell survival and mitochondrial bioenergetics, correlating with increased TFAM and vimentin-actin (VA) expression, indicative of a profibrotic phenotype.

Conclusions:

• TGF-β1 modulates mitochondrial responses to arecoline-induced cytotoxicity, promoting fibroblast survival and a profibrotic phenotype.
• Increased TFAM and VA-positive fibroblasts in advanced OSMF clinical samples corroborate in vitro findings.
• Targeting mitochondria in surviving myofibroblasts presents a potential novel therapeutic strategy for OSMF.