Lactate-induced mitochondrial calcium uptake 3 aggravates myocardial ischemia–reperfusion injury by promoting neutrophil extracellular trap formation

Background

Ischemic heart disease (IHD) remains a leading cause of mortality and disability worldwide. Although reperfusion therapies like PCI can effectively restore blood supply to the myocardium, their potential side effects, such as myocardial ischemia–reperfusion injury (MIRI), pose challenges to the application of these treatment strategies. 

Neutrophils generate neutrophil extracellular traps (NETs) in response to MIRI. However, research on the activation of NETs and their specific mechanisms of action in MIRI remains currently limited and requires further exploration. 

Research Progress

In order to elucidate the mechanisms underlying NET activation and its impact on MIRI, Hongru Zhang/Senlei Xu of Nanjing University of Chinese Medicine (NJUCM), along with Yanfei Mo of Pukou Hospital of Chinese Medicine, confirm that the generation of NETs by neutrophils exacerbates microvascular endothelial cell injury, thereby worsening MIRI.

Analysis revealed significant upregulation of the mitochondrial calcium uptake regulator MICU3 during MIRI. Subsequent validation established that MICU3 promotes mitochondrial Ca²⁺ uptake, mitophagy and NET formation. To further investigate the regulatory mechanism of MICU3 on NET formation, ​the experimental evidence performed IP-MS to identify the binding protein VDAC1. ​The study demonstrated that the interaction between MICU3 and VDAC1 facilitates mitochondrial Ca²⁺ uptake, causing mitochondrial dysfunction that leads to mitophagy and NET generation. 

Further investigation defined upstream regulatory mechanisms: lactate enhances MICU3 transcription via H3K18 lactylation (H3K18lac). Additionally, AARS1 was found to bind MICU3, catalyzing its lactylation to increase protein stability.

Results and Significance

The study reveals that MICU3-mediated mitochondrial calcium uptake, mitophagy and the subsequent activation of NETs play a key role in exacerbating MIRI. NETs contribute not only to microvascular dysfunction but also directly to myocardial cell injury, providing a more comprehensive understanding of their pathological role in MIRI.

Sources: https://spj.science.org/doi/10.34133/research.0705