What question did this study set out to answer?

This research aims to develop a peptide that targets MAMs to restore autophagy and improve atherosclerosis outcomes.

May 7, 2026Open Access

A MAM-targeting therapeutic peptide restores autophagy homeostasis and ameliorates atherosclerosis

Key Points

This research aims to develop a peptide that targets MAMs to restore autophagy and improve atherosclerosis outcomes.
Designed cell-permeable MAM-targeting peptides based on structural analyses of IP3 R-GRP75 complex.
Assessed peptide efficacy through cellular assays and in vivo studies in Western diet-fed ApoE -/- mice.
Conducted various analyses including thermal shift assays, co-immunoprecipitation, Ca2+ imaging, and autophagy flux assessments.
Peptide 4 effectively disrupted the IP3 R-GRP75 interaction and altered calcium transfer, leading to improved autophagy.
In vivo studies showed significant improvements in serum lipid profiles and reduced aortic plaque formation in treated mice.
Restoration of MAM architecture correlated with enhanced autophagy and lipid clearance, indicating its potential as a therapeutic target.

Abstract

Rationale: Mitochondria-associated ER membranes (MAMs) are critical hubs for Ca 2+ signaling, energy homeostasis, and autophagy.Their dysregulation contributes to lipid-driven cardiovascular diseases; however, selective and reversible strategies to modulate MAM-associated protein-protein interactions (PPIs) remain limited.This study aimed to develop a targeted peptide to disrupt the IP 3 R-GRP75-VDAC1 complex and evaluate its therapeutic efficacy in atherosclerosis.Methods: Based on structural and interface analyses of the IP 3 R-GRP75 complex, we designed cell-permeable MAM-targeting peptides.The activity of the lead candidate, Peptide 4, was assessed using proximity ligation assays, microscale thermophoresis (MST) analysis, cellular thermal shift assays, co-immunoprecipitation, live-cell Ca 2+ imaging, and autophagy flux analyses in endothelial cells and macrophages under basal and oxidized low-density lipoprotein (oxLDL)-induced stress.The therapeutic efficacy was further evaluated in Western diet-fed ApoE -/-mice.Results: Peptide 4 bound to GRP75, disrupted the IP 3 R-GRP75 interaction, and selectively attenuated ER-to-mitochondria Ca 2+ transfer.This controlled Ca 2+ modulation modestly reduced cellular ATP levels, activated the AMPK-TFEB axis, and restored functional autophagic flux.These effects were preserved under oxLDL-induced lipid stress.Restoration of MAM architecture closely correlated with autophagy recovery and lipid clearance, indicating its potential utility as a pharmacodynamic indicator.In vivo, systemic administration of Peptide 4 significantly improved serum lipid profiles, attenuated aortic plaque formation, reduced cardiac lipid deposition, and normalized MAM architecture in ApoE -/-mice.Conclusions: Our findings identify peptide-mediated targeting of the IP 3 R-GRP75 interaction as a promising strategy to modulate MAM structure, activate adaptive autophagy, and alleviate atherosclerotic pathology.This study supports organelle contact site modulation as both a therapeutic mechanism and a measurable disease-responsive feature, highlighting peptide-based modulation of protein-protein interactions as a promising approach for metabolic and cardiovascular diseases.

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