Abstract

Methamphetamine (METH)-induced cardiomyocyte injury is the leading cause of mortality beyond acute intoxication. METH abuse often occurs in crowded, poorly ventilated environments, and even moderately high ambient temperatures exacerbate METH-related cardiovascular emergencies. However, the underlying mechanisms by which environmental factors drive the progression of cardiac diseases remain poorly understood. This study modeled the real-world scenario in vivo by exposing mice to METH under normothermic condition (NC, 22 °C) or subthreshold thermal stress (STS, 28 °C, a mild thermal challenge for mice) conditions, and in vitro by using H9c2 cardiomyocytes exposed to METH at 37 °C or 39 °C. STS significantly potentiated METH-induced cardiac dysfunction, mitochondrial ultrastructural damage, and oxidative stress ( p < 0.05). Mechanistically, the co-exposure impaired mitochondrial respiratory chain complex I and led to excessive mitochondrial ROS (mtROS) production, activating the pro-apoptotic protein BAX, causing mitochondrial outer membrane (MOM) permeabilization and the cytosolic release of mitochondrial DNA (mtDNA). Cytosolic mtDNA-mediated NLRP3 inflammasome activation subsequently executed cardiomyocyte pyroptosis via caspase-1/Gasdermin D ( p < 0.05). Crucially, the mitochondria-targeted antioxidant mitoquinone (MitoQ) substantially attenuated the aggravated cardiotoxicity by scavenging the initial mtROS ( p < 0.05), thereby preventing the activation of the downstream BAX/mtDNA/NLRP3 axis. These findings provide evidence for a defined signaling basis for this drug-environment interaction and highlight mitochondrial redox modulation as a potential therapeutic strategy for psychostimulant-associated cardiovascular injury.