Alterations of Mitochondrial Structure in Methamphetamine Toxicity

Abstract

Recent evidence shows that methamphetamine (METH) produces mitochondrial alterations that contribute to neurotoxicity. Nonetheless, most of these studies focus on mitochondrial activity, whereas mitochondrial morphology remains poorly investigated. In fact, morphological evidence about the fine structure of mitochondria during METH toxicity is not available. Thus, in the present study we analyzed dose-dependent mitochondrial structural alterations during METH exposure. Light and transmission electron microscopy were used, along with ultrastructural stoichiometry of catecholamine cells following various doses of METH. In the first part of the study cell death and cell degeneration were assessed and they were correlated with mitochondrial alterations observed using light microscopy. In the second part of the study, ultrastructural evidence of specific mitochondrial alterations of crests, inner and outer membranes and matrix were quantified, along with in situ alterations of mitochondrial proteins. Neurodegeneration induced by METH correlates significantly with specific mitochondrial damage, which allows definition of a scoring system for mitochondrial integrity. In turn, mitochondrial alterations are concomitant with a decrease in fission/mitophagy protein Fis1 and DRP1 and an increase in Pink1 and Parkin in situ, at the mitochondrial level. These findings provide structural evidence that mitochondria represent both direct and indirect targets of METH-induced toxicity

Parents’ Knowledge, Attitude, and Practices toward Methamphetamine Abuse among Youth and its Risk Factors in Saudi Arabia

“…Symptoms such as amphetamine cravings, heightened hunger, agitation, cognitive impairment, weariness, physical discomfort, disrupted sleep patterns, intense dreams and nightmares, anxiety, depressive episodes, and paranoid ideation have been reported. [ 19 20 ]…”

Methamphetamine exposure drives cell cycle exit and aberrant differentiation in rat hippocampal-derived neurospheres

“…Moreover, aberrant cerebral hemodynamics as well as neurotransmitter release and uptake are also thought to be involved in METH-caused neurodevelopmental toxicity ( Dixon, 1989 ; Sankaran et al, 2022 ). At the cellular level, METH-caused neurotoxicity and degenerative effects correlate with oxidative stress/mitochondrial damage ( Wong et al, 2008 ; Potula et al, 2010 ; Lenzi et al, 2022 ) and cell cycle dysregulation ( Jackson et al, 2014 ; Fisher et al, 2015 ; Potula et al, 2018 ). In this study, through 3D cultured rat neurospheres, we also found that METH exposure caused dysregulation of the cell cycle in neurospheres.…”

“…Previous observations suggest a time/dose-dependent effect of METH on the brain ( Davidson et al, 2022 ). Due to the timeline of neurosphere proliferation and differentiation, it was challenging to expose METH at low concentrations for a longer period in order to generate toxicity ( Lenzi et al, 2022 ). Furthermore, according to the previous in vitro study, acute high doses of METH induced dopaminergic neuronal autophagy and apoptosis by increasing DNA damage-inducible transcript 4 (DDIT4) expression leading to neurotoxicity.…”

“…Growing evidence has discovered that METH exposure negatively impacts the neurogenesis of hippocampal neural stem cells in rodents ( Takashima and Mandyam, 2018 ). At the cellular level, METH-caused neurotoxicity and degenerative effects correlate significantly with specific mitochondrial damage, including damaged mitochondrial morphology, decreased mitochondrial membrane potential, and accumulated oxidative stress ( Wong et al, 2008 ; Potula et al, 2010 ; Lenzi et al, 2022 ). In addition to the oxidative stress-induced damage by acting on mitochondria, METH-caused toxicity also involves cell cycle dysregulation in diverse cells, including endothelial cells ( Fisher et al, 2015 ), lymphocyte T ( Potula et al, 2018 ), and DG astrocytes ( Jackson et al, 2014 ).…”

Mitochondrial dysfunction and autophagy activation are associated with cardiomyopathy developed by extended methamphetamine self-administration in rats

“…Defects in mitochondrial metabolism and energy production contributed to HF development under diverse pathological conditions, i.e., ischemia-reperfusion injury, pressure overload, lipid toxicity, and cardiotoxic drugs [ 40 , [90] , [91] , [92] ]. Previous studies reported METH exposure induces mitochondrial dysfunctions in both cardiovascular and neurological systems [ 28 , [93] , [94] , [95] ]. We have previously reported reduced mitochondrial respiration in mice heart mitochondria exposed for 4-weeks of intraperitoneal dose-escalated ‘binge and crash’ METH paradigm [ 23 ].…”