MOTS-c attenuates hyperoxia-induced neonatal cardiac injury by inhibiting oxeiptosis via maintaining the KEAP1-PGAM5 interaction.
This study investigated whether the mitochondrial-derived peptide MOTS-c could protect the neonatal heart from hyperoxia-induced injury. Using neonatal mice exposed to 85% oxygen as an in vivo model and the rat cardiomyocyte cell line H9C2 as an in vitro model, researchers found that hyperoxia caused cardiac hypertrophy, fibrosis, and dysfunction, alongside reduced circulating MOTS-c levels. Administration of MOTS-c was reported to markedly reduce these pathological changes and restore cardiac function in the mouse model. Mechanistically, the study found that hyperoxia activates a KEAP1–PGAM5–AIFM1 signaling axis, triggering a ROS-specific form of programmed cell death called oxeiptosis. MOTS-c appeared to interact directly with KEAP1, preserving its binding to PGAM5 and thereby preventing nuclear translocation of AIFM1, the downstream executioner of oxeiptosis. Overexpression of KEAP1 abolished MOTS-c's protective effects, supporting KEAP1 as a key target. Limitations include exclusive reliance on animal and cell-line models with no human data, a relatively narrow mechanistic focus, and the absence of long-term outcome measures. These findings are preclinical and require validation in human studies before clinical conclusions can be drawn.
Why this grade: All experimental data were generated exclusively in neonatal mice and a rat cardiomyocyte cell line (H9C2), with no human subjects or clinical data included.
Aims Hyperoxia-induced oxidative stress is a primary cause of neonatal injury. Neonatal heart shows a particular susceptibility to hyperoxic toxicity, yet mechanisms and effective therapeutic strategies remain limited. Oxeiptosis is a ROS-specific programmed cell death. Mitochondrial-derived peptide MOTS-c possesses well-known anti-oxidative effect. This study investigated the cardio-protective role of MOTS-c in hyperoxia exposed neonatal mice and its mechanism. Main methods Neonatal mice exposed hyperoxia (85% O 2 ) were used to establish the hyperoxic cardiac injury model. Additionally, the rat cardiomyocyte cell line H9C2 were subjected to hyperoxic conditions as an in vitro model. Serum MOTS-c content was measured using enzyme-linked immunosorbent assay. Hematoxylin and eosin staining, Real-time PCR, Western blotting, immunohistochemistry, and immunofluorescence techniques were employed to evaluate the effects of MOTS-c on hyperoxia-induced cardiac insufficiency. Key findings We found that hyperoxia exposure in neonatal mice led to significant cardiac hypertrophy, fibrosis, and dysfunction, concomitant with decreased serum MOTS-c content. Administration of MOTS-c markedly ameliorated these pathological changes and restored cardiac function. In vitro and in vivo experiments revealed that hyperoxia triggers oxidative stress and oxeiptosis via activating KEAP1-PGAM5-AIFM1 axis, and MOTS-c inhibited oxeiptosis. Mechanistically, MOTS-c could potentially interact with KEAP1, thereby maintaining the KEAP1-PGAM5 interaction, and inhibiting the downstream nuclear translocation of AIFM1. Notably, KEAP1 overexpression abrogated the protective effects of MOTS-c, confirming KEAP1 as a critical target of MOTS-c in hyperoxia-induced cardiac injury. Significance MOTS-c attenuates hyperoxic cardiac injury by inhibiting KEAP1-mediated oxeiptosis, highlighting its potential as a novel therapeutic agent for neonatal cardiomyopathy.
Educational summary of published research — not medical advice. Full text is shown only where licensing permits.