# Cocaine and HIV Influence Mitochondrial Epigenetics in Astrocytic Networks

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2021 · $481,922

## Abstract

Project Summary/Abstract
Astrocytes are the major regulators for energy storage, utilization and metabolic function in the central nervous
system (CNS). Cocaine abuse and HIV infections are significant risk factors for disrupting brain energy
metabolism and cocaine abuse is strongly associated with HIV-1 infection and a subsequent development of
AIDS. The proposed research is aimed at investigating the effects of cocaine and HIV-Transactivator protein
(HIV-Tat) on astrocyte energy metabolism and associated neuronal impairments. Altered DNA methylation in
the region of the mitochondrial genome encoding the NADH dehydrogenase (NDH-
displacement loop (D-loop)
Family) subunits (ND1-ND6) plays a critical role in energy storage and utilization by regulating the energy
source of brain metabolism to preserve CNS cell functions. Therefore, we investigated the role of cocaine
and/or HIV-1 infection on the mitochondrial epigenetic mechanisms that alters the astrocytic energy
metabolism. Moreover, the role of mitochondrial DNA methyl transferases (mtDNMTs) in impacting energy
deficits in astrocytes leading to neuronal impairment has never been elucidated in the context of either cocaine
or HIV-Tat, or in combination. Our preliminary studies showed that cocaine and/or HIV-1 Tat targets DNMTs
and mtDNMTs (mtDNMT1, mtDNMT3A and mtDNMT3B) with concomitant activation of mitochondrial
biogenesis in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) that is known to
regulate mtDNA synthesis and control energy metabolism affecting neuro plasticity and spine density. We thus
hypothesize that cocaine acts as a co-factor in the neuropathogenesis of HIV-Tat by activating DNMTs
expression in astrocytes leading to energy deficits and impacting DNA methylation and mitochondrial
biogenesis. These epigenetic mechanisms are mediated by
of
5-methylcytosine (5-mC), 5-hydroxymethylcytosine (5hmC)
the regulatory D-loop region and its effect
and ten-eleven translocation (TET) family
dioxygenases
, which affect energy transfer into neurons and dysregulate neuro plasticity, spine density
and cell growth. Accordingly, in the specific Aim # 1A we will examine whether cocaine in association with
HIV-Tat affect energy dysfunction of astrocytes and impacts DNMTs, mtDNMTs and biogenesis-led energy
transfer, in Aim 1B# we propose to determine the effect on neuroplasticity/ axons/ dendrites formation and cell
growth in primary neurons thereby contributing to neuronal death; the specific Aim # 2, we will validate the
mechanistic study involving cocaine exposure of HIV-Tat (GT-tg) transgenic mice to investigate the mtDNMTs
role in energy metabolism, and whether piracetam (a
neuro-protective agent)
treatment reverses the effects of
cocaine and HIV-Tat on mtDNMTs leading to neuro plasticity and axons/ dendrites formation to develop a
therapeutic strategy regulating energy metabolism impacting neurotoxicity. An understanding of cocaine and
HIV-associated astrocytes ene...

## Key facts

- **NIH application ID:** 10219215
- **Project number:** 5R01DA044872-06
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Samikkannu Thangavel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $481,922
- **Award type:** 5
- **Project period:** 2017-09-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219215

## Citation

> US National Institutes of Health, RePORTER application 10219215, Cocaine and HIV Influence Mitochondrial Epigenetics in Astrocytic Networks (5R01DA044872-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10219215. Licensed CC0.

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