Targeting AMPK signaling in ischemic/reperfusion injury: From molecular mechanism to pharmacological interventions

Mahshid Deldar Abad Paskeh, Ava Asadi, Sepideh Mirzaei, Mehrdad Hashemi, Maliheh Entezari, Rasoul Raesi, Kiavash Hushmandi, Ali Zarrabi, Yavuz Nuri Ertas, Amir Reza Aref, Saeed Samarghandian, Russel J. Reiter, Jun Ren

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Ischemia is a pathological process in which blood supply to a particular organ is temporarily interrupted resulting in disturbed biological function and homeostasis of local tissues. Following ischemia, reperfusion and reoxygenation may occur which further worsens oxidative stress-mediated damage in cells and tissues. The combined processes are referred to as ischemia/reperfusion (I/R) injury. Immediate management and treatment of I/R is of utmost importance for preventing irreversible and extensive cellular damage. Apoptosis, inflammation and oxidative stress are the most validated pathologies associated with I/R. AMP-activated protein kinase (AMPK) modulates energy metabolism in cells and its activation occurs in response to elevated AMP and ADP levels. Aberrant levels of AMPK are noted in various pathological settings such as diabetes mellitus, cancer and neurological diseases. This review emphasizes AMPK signaling, its related molecular pathways and therapeutic utility during I/R. Activation of AMPK through phosphorylation prevents apoptosis and reduces oxidative stress and inflammation upon I/R. Inducing AMPK signaling normalizes mitochondrial function to inhibit cell death. Autophagy as a cytoprotective mechanism undergoes activation by AMPK/mTOR and AMPK/ULK1 pathways. AMPK reinforces the antioxidant defense capacity via Nrf2 signaling to counteract oxidative stress in I/R. Protective compounds including phytochemicals activate AMPK to alleviate I/R injury.

Original languageEnglish (US)
Article number110323
JournalCellular Signalling
Volume94
DOIs
StatePublished - Jun 2022

Keywords

  • AMPK
  • Apoptosis
  • Autophagy
  • Cell death
  • Ischemia/reperfusion injury
  • Oxidative stress

ASJC Scopus subject areas

  • Cell Biology

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