MOTS-c, a mitochondrial-derived peptide, ameliorates lysosomal membrane permeability and improves survival of soft tissue transplantation

MOTS-c improved survival of ischemic soft tissue flaps by reducing lysosomal membrane permeabilization and endothelial pyroptosis. It suppressed PLA2G4A phosphorylation through the MAPK1-MAPK3-NFKB signaling axis, thereby enhancing autophagy and restoring cellular homeostasis.

Journal article — preclinical animal and cell study. Population: ischemic soft tissue flaps in vivo and HUVECs in vitro. Interventions: MOTS-c.

MOTS-c treatment improved blood flow perfusion, enhanced angiogenesis and collagen remodeling, and increased flap survival in ischemic flaps. It reduced endothelial pyroptosis, enhanced autophagy, and attenuated lysosomal membrane permeabilization. Mechanistically, MOTS-c inhibited PLA2G4A phosphorylation through the MAPK1-MAPK3-NFKB signaling cascade. Overexpression of PLA2G4A via AAV in vivo reversed these protective effects, confirming the pathway's role.

This paper links MOTS-c to lysosomal membrane integrity and pyroptosis, expanding its known cytoprotective roles beyond mitochondrial function. It identifies PLA2G4A as a downstream effector and the MAPK1-MAPK3-NFKB axis as a mediator, providing a mechanistic basis for future work on MOTS-c in ischemia and transplantation. It does not establish clinical efficacy, dosage, or safety in humans.

Key findings

• MOTS-c treatment improved blood flow perfusion in ischemic flaps compared with untreated controls.
• MOTS-c reduced endothelial pyroptosis, enhanced autophagy, and attenuated lysosomal membrane permeabilization.
• MOTS-c suppressed PLA2G4A phosphorylation via the MAPK1-MAPK3-NFKB signaling cascade.
• In vivo overexpression of PLA2G4A via AAV reversed MOTS-c's protective effects, confirming PLA2G4A as a key target.
• MOTS-c increased angiogenesis and collagen remodeling, as shown by histological staining.
• MOTS-c enhanced flap survival in the ischemic flap model.

Limitations

• Authors did not state limitations; findings are from experimental models and may not translate directly to humans.
• No sample sizes or statistical effect sizes are reported in the abstract.
• The study does not address dosing, route, or clinical safety of MOTS-c.
• Detailed time-course and long-term outcomes are not described in the abstract.

The record

• Journal: Autophagy: 1-30
• Published: 2026-05-19
• PMID: 42153537 — DOI: 10.1080/15548627.2026.2677180
• Author countries: China

Peptide profiles: MOTS-c.

All indexed evidence: MOTS-c trials & papers.

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