Mitochondrial CircRNA CircMT-RNR2 Safeguards Antioxidant Defense to Support Fibroblast Functions in Wound Repair

Area of Science:

• Mitochondrial biology
• RNA biology
• Dermatology

Background:

• Diabetic foot ulcers (DFUs) are a major diabetes complication.
• Mitochondrial dysfunction and oxidative stress are key but unresolved features of DFUs.
• Understanding molecular mechanisms in DFU pathogenesis is critical for effective treatment.

Purpose of the Study:

• To identify novel regulators of mitochondrial redox homeostasis in skin wound healing.
• To investigate the role of mitochondria-encoded circular RNAs (mecciRNAs) in DFUs.
• To explore circMT-RNR2 as a potential therapeutic target for DFU treatment.

Main Methods:

• Quantification of circMT-RNR2 in human DFU tissues and diabetic mouse wounds.
• Localization studies of circMT-RNR2 in dermal fibroblasts and mitochondria.
• Functional assays assessing fibroblast behavior (proliferation, migration, ECM production, contraction) upon circMT-RNR2 modulation.
• Assessment of oxidative stress markers, mitochondrial integrity, and mitophagy.
• In vivo and ex vivo wound healing models (murine and human).

Main Results:

• CircMT-RNR2 levels are reduced in DFU patient tissue and diabetic mouse wounds.
• CircMT-RNR2 is localized to mitochondria within dermal fibroblasts.
• Loss of circMT-RNR2 impairs fibroblast function and promotes oxidative stress, mitochondrial damage, and mitophagy by destabilizing PRDX3.
• Knockdown of circMT-RNR2 delays wound healing in murine and human ex vivo models.
• Overexpression of circMT-RNR2 accelerates wound repair and enhances antioxidant defenses.

Conclusions:

• CircMT-RNR2 acts as a novel modulator of mitochondrial redox homeostasis in skin wound healing.
• Reduced circMT-RNR2 contributes to the pathogenesis of diabetic foot ulcers.
• CircMT-RNR2 is a promising mitochondrial guardian and therapeutic target for accelerating DFU repair.