What does this research mean for the field?

The HIF-1α/Drp1 signaling axis drives mitochondrial dysfunction and cellular senescence in acute myocardial infarction, and inhibiting this pathway or the associated senescence-associated secretory phenotype (SASP) mitigates myocardial injury. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This study aims to identify the role of the HIF-1α/Drp1 axis in regulating mitochondrial dysfunction and senescence-like changes after acute myocardial infarction (AMI).

June 1, 2026Open Access

Inhibiting the Hif-1α-Drp1 axis alleviates mitochondrial dysfunction and reduces senescence-like changes in myocardial tissue after acute myocardial infarction

Puntos clave

This study aims to identify the role of the HIF-1α/Drp1 axis in regulating mitochondrial dysfunction and senescence-like changes after acute myocardial infarction (AMI).
In vivo rat AMI model and in vitro hypoxia-exposed H9c2 cardiomyocyte assessments were conducted.
Genetic gain- and loss-of-function methods were used to modulate HIF-1α and Drp1.
Mdivi-1 and Ruxolitinib were tested as interventions to evaluate their effects on mitochondrial function and senescence.
AMI/hypoxia activates ERK1/2-Akt pathway, leading to Drp1 Ser616 phosphorylation and mitochondrial dysfunction (p<0.05).
Mdivi-1 restored mitochondrial dynamics and improved cardiac function, reducing SASP-related inflammation (p=0.01).
Ruxolitinib suppressed Drp1 phosphorylation and alleviated senescence and apoptosis, exhibiting significant protective effects.

Resumen

BACKGROUND: Cellular senescence is a significant pathological process in acute myocardial infarction (AMI), yet its upstream regulatory mechanisms remain unclear. This study reveals that the HIF-1α /Drp1 signaling axis serves as a critical link between hypoxia and senescence-like changes in myocardial tissue by disrupting mitochondrial homeostasis. METHODS: Using rat AMI model (in vivo) and hypoxia‑exposed H9c2 cardiomyocytes (in vitro), we assessed mitochondrial morphology, mtROS, and senescence markers. Genetic gain‑ and loss‑of‑function approaches were applied to modulate Drp1 and HIF‑1α. We further evaluated the effects of the mitochondrial fission inhibitor Mdivi‑1 and the SASP inhibitor Ruxolitinib on mitochondrial function, senescence, and apoptosis. RESULTS: AMI/hypoxia activated the ERK1/2-Akt pathway, promoting Drp1 Ser616 phosphorylation and mitochondrial translocation, leading to excessive fission, mtROS burst, and senescence-like changes in myocardial tissue (in vivo) / cardiomyocyte senescence (in H9c2 cells). HIF-1α transcriptionally regulated Drp1 expression. Mdivi-1 restored mitochondrial dynamics, reduced SASP-related inflammation, and improved cardiac function, indicating a myocardial protective effect. Ruxolitinib suppressed Drp1 Ser616 phosphorylation and alleviated senescence, apoptosis, and pyroptosis. CONCLUSION: HIF-1α-mediated upregulation of Drp1 and ERK-dependent phosphorylation of Drp1 collectively drive mitochondrial dysfunction and senescence-like changes in myocardial tissue in AMI. Targeting these pathways or the SASP pathway represents a promising therapeutic strategy.

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