MOTS-c peptide improves soft tissue transplant survival by reducing lysosomal membrane permeability and pyroptosis

Reconstructive surgery faces a significant challenge with distal ischemic necrosis, where inadequate blood supply leads to tissue death. Cellular homeostasis relies on intricate interactions between mitochondria and lysosomes. Mitochondrial dysfunction can compromise lysosomal integrity, leading to lysosomal membrane permeabilization (LMP), a critical event in cell death pathways. MOTS-c, a mitochondrial-derived peptide, is known to enhance mitochondrial function by reducing reactive oxygen species (ROS) and stabilizing membrane potential. This study explores if MOTS-c can leverage these benefits to preserve lysosomal integrity and improve outcomes in ischemic conditions.

This study investigated the protective effects of MOTS-c in an ischemic flap model (species not specified, likely rodent). Researchers employed RNA sequencing to explore underlying mechanisms. Blood flow perfusion was assessed using tissue clearing, laser speckle contrast imaging, and Doppler analyses. Histological analyses, including HE, Masson, and F-CHP staining, evaluated angiogenesis and collagen remodeling. Western blotting, ELISA, and immunofluorescence were used to quantify pyroptosis, macroautophagy/autophagy, LMP, and key proteins in the MAPK1/ERK2-MAPK3/ERK1-NFKB/NF-κB pathway. In vivo overexpression of PLA2G4A/cPLA2 via AAV confirmed its role in MOTS-c's mechanism.

MOTS-c treatment significantly improved blood flow perfusion in ischemic flaps, as revealed by tissue clearing, laser speckle contrast imaging, and Doppler analyses. Histological staining further demonstrated enhanced angiogenesis and beneficial collagen remodeling. Mechanistically, MOTS-c consistently reduced endothelial pyroptosis, enhanced autophagy, and attenuated lysosomal membrane permeabilization (LMP) within the ischemic flap tissues. These protective effects were linked to specific molecular actions: In vivo overexpression of PLA2G4A/cPLA2 confirmed that MOTS-c enhances autophagy and reduces pyroptosis and LMP by suppressing PLA2G4A phosphorylation. Furthermore, the study elucidated that MOTS-c inhibited PLA2G4A activity through modulation of the MAPK1-MAPK3-NFKB signaling cascade. This suppression of PLA2G4A ultimately led to a reduction in LMP and a notable improvement in overall flap survival, highlighting a novel therapeutic axis.