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

Background: Methamphetamine (Meth) is a potent psychoactive stimulant that triggers complex neurotoxicity characterized by autophagy-associated neuronal death. However, the potential mechanisms remain poorly understood. This study aimed to decipher the Meth-induced neuronal necroptosis involving mitochondrial defect-initiated excessive mitophagy caused by aberrant presenilin-associated rhomboid-like (PARL) cleavage of PTEN-induced kinase 1 (PINK1) and phosphoglycerate mutase family member 5 (PGAM5).

Methods And Results: With the transcriptome analysis, Meth exposure significantly affected autophagy, mitophagy, and necroptosis pathways; meanwhile, the proteomic analysis revealed a marked decline in the level of PARL, which led to an imbalance in intramembrane proteolysis of PINK1 and PGAM5. In behavioral tests, Meth administration elicited pronounced cognitive decline in mice, accompanied by decreased neuronal numbers, massive autophagosomes, and mitochondrial fragmentation, and these processes can be dramatically reversed by knockin of PARL and knockdown of PGAM5 in the mouse hippocampus, molecularly manifesting as decreased necrosome formation and phosphorylated mixed lineage kinase domain-like (p-MLKL) mitochondrial membrane translocation, and improved autophagic flux.

Conclusion: In summary, these findings collectively underscore the key roles of the PARL-PGAM5 axis in Meth-mediated neuronal necroptosis and that targeting this axis may provide promising therapeutic strategies for mitigating Meth-induced neurotoxicity.