HIV-1 Tat and cocaine impact mitochondrial epigenetics: effects on DNA methylation

Abstract

Human immunodeficiency virus (HIV) infection and the psychostimulant drug cocaine are known to induce epigenetic changes in DNA methylation that are linked with the severity of viral replication and disease progression, which impair neuronal functions. Increasing evidence suggests that changes in DNA methylation and hydroxymethylation occur in mitochondrial DNA (mtDNA) and represent mitochondrial genome epigenetic modifications (mitoepigenetic modifications). These modifications likely regulate both mtDNA replication and gene expression. However, mtDNA methylation has not been studied extensively in the contexts of cocaine abuse and HIV-1 infection. In the present study, epigenetic factors changed the levels of the DNA methyltransferases (DNMTs) DNMT1, DNMT3a, and DNMT3b, the Ten-eleven translocation (TET) enzymes 1, 2, and 3, and mitochondrial DNMTs (mtDNMTs) both in vitro and in vivo. These changes resulted in alterations in mtDNA methylation levels at CpG and non-CpG sites in human primary astrocytes as measured using targeted next-generation bisulphite sequencing (TNGBS). Moreover, mitochondrial methylation levels in the MT-RNR1, MT-ND5, MT-ND1, D-loop and MT-CYB regions of mtDNA were lower in the HIV-1 Tat and cocaine treatment groups than in the control group. In summary, the present findings suggest that mitoepigenetic modification in the human brain causes the mitochondrial dysfunction that gives rise to neuro-AIDS.

Mitochondrial DNA Methylation and Human Diseases

“…Global 5-mC and 5-hmC mtDNA content Global hypomethylation of mtDNA in fructose-fed rats as well as higher mtDNA content and transcription of several mtDNA genes [116] It has been reported that mtDNA methylation is modulated by exposure to particulate matter (PM 1 and PM 2.5 ), air benzene, traffic-derived elemental carbon [56,108,113], particle-containing welding fumes [120], endocrine disruptors [109], maternal smoking [112,118,129], chrome [117], arsenic [59] and iron [121], as well as to the pharmacological agent valproic acid [51], to the demethylating agents 5-azacytidine and vitamin C [70,122] and to HIV infection and cocaine [125]. Variations in mtDNA methylation patterns have also been associated with various endogenous metabolites, including thyroid hormones [119], homocysteine [114,126], betaine [110], glucose [79,80], L-carnitine [124], lipopolysaccharides [127] and mitochondrial-derived peptides [123].…”

Psychostimulants and opioids differentially influence the epigenetic modification of histone acetyltransferase and histone deacetylase in astrocytes

“…Piracetam, cocaine, METH and morphine were prepared in cell culture-grade distilled water to obtain working concentrations. To investigate the effects of cocaine, METH, morphine and piracetam, the cultured cells were divided into eight groups: (i) control cells exposed to media alone, (ii) piracetam (10 μM), (iii) cocaine (1 μM), (iv) piracetam and cocaine, (v) METH (10 μM), (vi) piracetam and METH, (vii) morphine (5 μM), and (viii) piracetam and morphine for 24 h. The doses used in this study were based from our previous published studies [36][37][38][39]. Cocaine (1 μM), METH (10 μM), morphine (5 μM) and piracetam (10 μM) did not show any toxicity at particular mentioned concentrations.…”

Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments

“…It was observed that Tat remained near to the mitochondria [ 57 , 58 ], suggesting cellular distribution is related to organelle alterations. Accordingly, other findings revealed that Tat-exposed cells present mtDNA damage [ 20 , 59 ] and alteration in its methylation patterns [ 60 ], mitochondrial membrane potential reduction [ 23 ] changes in size and morphology of the organelle, fusion-fission triggering [ 24 ], increased mitochondrial ROS [ 61 , 62 ], mitophagy disruption [ 17 , 57 ], mitochondrial functions dysregulation [ 17 , 61 ] calcium homeostasis disturbance [ 61 , 63 , 64 ], and apoptosis activation [ 23 , 58 , 61 , 65 , 66 ].…”