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Updated: May 25, 2025

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Cleaving PINK1 or PGAM5? Involvement of PARL in Methamphetamine-Induced Excessive Mitophagy and Neuronal Necroptosis

Di An1, Chuling Zhang2, Peng Zhou1

  • 1Department of Emergency, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

CNS Neuroscience & Therapeutics
|February 27, 2025
PubMed
Abstract

Insights

Methamphetamine neurotoxicity involves excessive mitophagy and neuronal death, driven by the PARL-PGAM5 axis. Targeting this pathway may offer new treatments for methamphetamine-induced brain damage.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Toxicology

Background:

  • Methamphetamine (Meth) causes neurotoxicity via autophagy-dependent neuronal death.
  • Mechanisms underlying Meth-induced neurotoxicity, particularly neuronal necroptosis, are not fully understood.

Purpose of the Study:

  • To investigate the role of presenilin-associated rhomboid-like (PARL) in Meth-induced neuronal necroptosis.
  • To elucidate the involvement of PTEN-induced kinase 1 (PINK1) and phosphoglycerate mutase family member 5 (PGAM5) in Meth neurotoxicity.

Main Methods:

  • Transcriptome and proteomic analyses to identify affected pathways and protein level changes.
  • Behavioral tests in mice to assess cognitive function and neuronal damage.
  • Genetic manipulation (PARL knockin, PGAM5 knockdown) in the mouse hippocampus.

Main Results:

  • Meth exposure altered autophagy, mitophagy, and necroptosis pathways, decreasing PARL levels.
  • Mice treated with Meth showed cognitive decline, neuronal loss, and mitochondrial fragmentation.
  • PARL restoration and PGAM5 reduction reversed these effects, decreasing necrosome formation and p-MLKL translocation.

Conclusions:

  • The PARL-PGAM5 axis is crucial in Meth-induced neuronal necroptosis.
  • Targeting the PARL-PGAM5 axis presents a potential therapeutic strategy for Methamphetamine neurotoxicity.
Keywords:
PARLPGAM5methamphetaminemitophagynecroptosis

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