Decreased mitochondrial DNA copy number in the hippocampus and peripheral blood during opiate addiction is mediated by autophagy and can be salvaged by melatonin

Abstract

Drug addiction is a chronic brain disease that is a serious social problem and causes enormous financial burden. Because mitochondrial abnormalities have been associated with opiate addiction, we examined the effect of morphine on mtDNA levels in rat and mouse models of addiction and in cultured cells. We found that mtDNA copy number was significantly reduced in the hippocampus and peripheral blood of morphine-addicted rats and mice compared with control animals. Concordantly, decreased mtDNA copy number and elevated mtDNA damage were observed in the peripheral blood from opiate-addicted patients, indicating detrimental effects of drug abuse and stress. In cultured rat pheochromocytoma (PC12) cells and mouse neurons, morphine treatment caused many mitochondrial defects, including a reduction in mtDNA copy number that was mediated by autophagy. Knockdown of the Atg7 gene was able to counteract the loss of mtDNA copy number induced by morphine. The mitochondria-targeted antioxidant melatonin restored mtDNA content and neuronal outgrowth and prevented the increase in autophagy upon morphine treatment. In mice, coadministration of melatonin with morphine ameliorated morphine-induced behavioral sensitization, analgesic tolerance and mtDNA content reduction. During drug withdrawal in opiate-addicted patients and improvement of protracted abstinence syndrome, we observed an increase of serum melatonin level. Taken together, our study indicates that opioid addiction is associated with mtDNA copy number reduction and neurostructural remodeling. These effects appear to be mediated by autophagy and can be salvaged by melatonin.

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

“…Consistent with previous observations that melatonin can restore morphine-induced autophagy 45 and kainic acid-induced autophagy, 61 we found that melatonin inhibited MPTP-induced autophagy and cell death in vitro. This salvaging effect of melatonin was CDK5-dependent, and knockdown or overexpression of CDK5 abolished the protective effect of melatonin on MPTP-induced autophagy and cell death.…”

“…Mouse cortical neurons were prepared and cultured using a previously described method. 45 Briefly, primary cortical neurons were isolated from mouse E15 embryos and were cultured in Neurobasal Ò Medium supplement with 2% B27 (Gibco-BRL, 17504).…”

“…Our recent study suggests that melatonin can restore the mitochondrial DNA copy number to normal level by inhibiting autophagy induced by morphine. 45 Based on these lines of evidence, we hypothesized that aberrant activation of autophagy may contribute to MPTP-induced neuronal cell death, which will lead to dopamine depletion in the striatum and motor symptoms of the PD animal models. We asked whether melatonin can reduce autophagic neuronal cell death induced by MPTP and which factor is mediating the process of dopaminergic neuronal cell loss and the bradykinesia of the PD animal models.…”

Inflammasome activation leads to Caspase-1–dependent mitochondrial damage and block of mitophagy

“…5B). The small increase in mtDNA accumulation is expected for the short time course, given ∼2× increases in mtDNA levels in models of prolonged and/or steady-state mitophagy deficiency/impairment (23). Collectively, these findings indicate that inflammasome activation leads to a Caspase-1-dependent block of mitophagy.…”

Fibroblast Growth Factor 21 Protects Against High Glucose Induced Cellular Damage and Dysfunction of Endothelial Nitric-Oxide Synthase in Endothelial Cells

“…Intracellular ROS production was evaluated using membrane-permeable probe DCFH-DA assay as described previously [34]. HUVECs were cultured in medium of normal glucose, high glucose and high glucose + FGF21 (30 nM) for 48 hours, and then washed with PBS followed by incubation in medium containing 20 µmol/L DCFH-DA at 37°C for 2 hours.…”