Methamphetamine Exposure Induces Neuronal Programmed Necrosis by Permeabilizing Mitochondria via the RIPK1-RIPK3-MLKL Axis.

ABSTRACT: Methamphetamine (Meth), a psychostimulant drug of the amphetamine type, is widely abused and highly neurotoxic. Meth exposure leads to neuronal necroptosis, and the mitochondrial dysfunction may be involved. However, the underlying mechanisms remain poorly understood. Here, we found that Meth significantly elicited the formation of the RIPK1-RIPK3-MLKL necrosome complex. Intriguingly, the activated MLKL (p-MLKL) translocated to the mitochondrial membrane and displayed pore-forming activity, manifesting as the penetration of MLKL in the cell membranes of the mitochondria, which caused decreased mitochondrial membrane potential, ATP generation, and mitochondrial DNA (mtDNA) and increased mitochondrial ROS (mtROS) generation, which finalized neuronal necroptosis. Notably, MLKL activation and

SUBMITTER: Zhou P 

PROVIDER: S-EPMC12473512 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature