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. Here, PGAM5 is linked to Mental deterioration.