Suppression of PCK1 attenuates neuronal injury and improves post-resuscitation outcomes

Abstract

Cardiac arrest (CA) is a critical medical emergency that can occur in both patients with preexisting conditions and otherwise healthy individuals. Despite successful resuscitation through cardiopulmonary resuscitation (CPR), many survivors are at significant risk of developing post-cardiac arrest syndrome (PCAS), a complex systemic response to CA that includes brain injury as a major component. Phosphoenolpyruvate carboxykinase 1 (PCK1), the first rate-limiting enzyme in gluconeogenesis, has been implicated in various diseases. However, its role in neuronal damage following CA/CPR remains unclear.

To investigate the role of PCK1 in neuronal damage after CA/CPR, we established the CA/CPR animal model and hypoxia/re‑oxygenation (H/R) cell model, manipulated PCK1 expression both in vivo and in vitro. We found increased expression of PCK1 in cortical neurons after CA/CPR. In vivo PCK1 overexpression exacerbated brain injury after CA/CPR via augmenting neuroinflammation and neuronal apoptosis. RNA-sequencing suggested PCK1-OE disturbed the neuronal metabolism while immunoprecipitation/mass spectrometry (IP/MS) revealed that PCK1 contributed to the mitochondrial dysfunction via binding to Voltage-dependent anion-selective channel 1 (VDAC1) and promoting its oligomerization and cytochrome c release. Besides, we confirmed that 3-Mercaptopicolinic acid (3-MPA), the PCK1 inhibitor, could ameliorate the mitochondrial dysfunction and apoptosis of neurons both in vitro and in vivo.

For the first time, we identified the detrimental role of PCK1 in post-CA brain injury. During CA/CPR, excessive PCK1 binds to VDAC1, promoting its oligomerization and cytochrome c release which leading to neuronal apoptosis and eventually PCAS. Utilization of 3-MPA during CPR could effectively improve the survival rate and prognosis of mice after CA, which may provide a novel strategy for CA/CPR treatment.