MOTS-c attenuates hyperoxia-induced neonatal cardiac injury by inhibiting oxeiptosis via maintaining the KEAP1-PGAM5 interaction.
MOTS-c appears to have a protective effect against hyperoxia-induced cardiac injury in neonatal mice, but its relevance to human conditions is not established.
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this study against the rest of the mots-c corpusSummary and findings
This study investigated the effects of MOTS-c on hyperoxia-induced cardiac injury in neonatal mice and rat cardiomyocyte cell lines. The findings indicated that MOTS-c administration ameliorated cardiac hypertrophy, fibrosis, and dysfunction associated with hyperoxia exposure. The study suggests a mechanism involving the inhibition of oxeiptosis through the KEAP1-PGAM5 interaction.
Abstract
<h4>Aims</h4>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.<h4>Main methods</h4>Neonatal mice exposed hyperoxia (85% O<sub>2</sub>) 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.<h4>Key findings</h4>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.<h4>Significance</h4>MOTS-c attenuates hyperoxic cardiac injury by inhibiting KEAP1-mediated oxeiptosis, highlighting its potential as a novel therapeutic agent for neonatal cardiomyopathy.