HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy

Annadurai Thangaraj, Palsamy Periyasamy, Ke Liao, Venkata Sunil Bendi, Shannon Callen, Gurudutt Pendyala, Shilpa Buch

Research output: Contribution to journalArticle

Abstract

While the advent of combination antiretroviral therapy (cART) has dramatically increased the life expectancy of HIV-1 infected individuals, paradoxically, however, the prevalence of HIV-1-associated neurocognitive disorders is on the rise. Based on the premise that the cytotoxic HIV-1 protein, transactivator of transcription (TAT), a known activator of glial cells that is found to persist in the central nervous system (CNS) despite cART, we sought to explore the role of defective mitophagy in HIV-1 TAT-mediated microglial activation. Our results demonstrated that exposure of mouse primary microglia to HIV-1 TAT resulted in cellular activation involving altered mitochondrial membrane potential that was accompanied by accumulation of damaged mitochondria. Exposure of microglia to HIV-1 TAT resulted in increased expression of mitophagy signaling proteins, such as PINK1, PRKN, and DNM1L, with a concomitant increase in the formation of autophagosomes, as evidenced by increased expression of BECN1 and MAP1LC3B-II. Intriguingly, exposure of cells to HIV-1 TAT also resulted in increased expression of SQSTM1, signifying thereby a possible blockade of the mitophagy flux, leading, in turn, to the accumulation of mitophagosomes. Interestingly, HIV-1 TAT-mediated activation of microglia was associated with decreased rate of extracellular acidification and mitochondrial oxygen consumption and increased expression of proinflammatory cytokines, such as Tnf, Il1b, and Il6. HIV-1 TAT-mediated defective mitophagy leading to microglial activation was further validated in vivo in the brains of HIV-1 transgenic rats. In conclusion, HIV-1 TAT activates microglia by increasing mitochondrial damage via defective mitophagy.

ABBREVIATIONS: 3-MA: 3-methyladenine; Δψm: mitochondrial membrane potential; ACTB: actin, beta; AIF1: allograft inflammatory factor 1; ATP: adenosine triphosphate; BAF: bafilomycin A1; BECN1: beclin 1, autophagy related; cART: combined antiretroviral therapy; CNS: central nervous system; DNM1L: dynamin 1 like; DMEM: Dulbecco modified Eagle medium; DAPI: 4,6-diamidino-2-phenylindole‎; ECAR: extracellular acidification rate; FBS: fetal bovine serum; FCCP: trifluoromethoxy carbonylcyanide phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAND: HIV-1-associated neurocognitive disorders; HIV-1 TAT: human immunodeficiency virus-1 transactivator of transcription; IL1B: interleukin 1, beta; IL6: interleukin 6; ITGAM: integrin subunit alpha M; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; mPMs: mouse primary microglial cells; MRC: maximal respiratory capacity; mt-CO1: mitochondrially encoded cytochrome c oxidase; mt-ND6: mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 6; NFKB1: nuclear factor kappa B subunit 1; NLRP3: NLR family pyrin domain containing 3; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TNF: tumor necrosis factor.

Original languageEnglish (US)
Pages (from-to)1596-1619
Number of pages24
JournalAutophagy
Volume14
Issue number9
DOIs
StatePublished - 2018

Fingerprint

Mitochondrial Degradation
Trans-Activators
HIV-1
Microglia
Central Nervous System
Mitochondrial Membrane Potential
Oxygen Consumption
Small Interfering RNA
Interleukin-6
CD11b Antigens
Dynamin I
Adenosine Triphosphate
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Transgenic Rats
Human Immunodeficiency Virus Proteins
Electron Transport Complex I
Eagles
Glyceraldehyde-3-Phosphate Dehydrogenases
Ubiquitin-Protein Ligases
Microtubule-Associated Proteins

Cite this

HIV-1 TAT-mediated microglial activation : role of mitochondrial dysfunction and defective mitophagy. / Thangaraj, Annadurai; Periyasamy, Palsamy; Liao, Ke; Bendi, Venkata Sunil; Callen, Shannon; Pendyala, Gurudutt; Buch, Shilpa.

In: Autophagy, Vol. 14, No. 9, 2018, p. 1596-1619.

Research output: Contribution to journalArticle

Thangaraj, Annadurai ; Periyasamy, Palsamy ; Liao, Ke ; Bendi, Venkata Sunil ; Callen, Shannon ; Pendyala, Gurudutt ; Buch, Shilpa. / HIV-1 TAT-mediated microglial activation : role of mitochondrial dysfunction and defective mitophagy. In: Autophagy. 2018 ; Vol. 14, No. 9. pp. 1596-1619.
@article{78a4e9e6766f4d129b867d325af3170d,
title = "HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy",
abstract = "While the advent of combination antiretroviral therapy (cART) has dramatically increased the life expectancy of HIV-1 infected individuals, paradoxically, however, the prevalence of HIV-1-associated neurocognitive disorders is on the rise. Based on the premise that the cytotoxic HIV-1 protein, transactivator of transcription (TAT), a known activator of glial cells that is found to persist in the central nervous system (CNS) despite cART, we sought to explore the role of defective mitophagy in HIV-1 TAT-mediated microglial activation. Our results demonstrated that exposure of mouse primary microglia to HIV-1 TAT resulted in cellular activation involving altered mitochondrial membrane potential that was accompanied by accumulation of damaged mitochondria. Exposure of microglia to HIV-1 TAT resulted in increased expression of mitophagy signaling proteins, such as PINK1, PRKN, and DNM1L, with a concomitant increase in the formation of autophagosomes, as evidenced by increased expression of BECN1 and MAP1LC3B-II. Intriguingly, exposure of cells to HIV-1 TAT also resulted in increased expression of SQSTM1, signifying thereby a possible blockade of the mitophagy flux, leading, in turn, to the accumulation of mitophagosomes. Interestingly, HIV-1 TAT-mediated activation of microglia was associated with decreased rate of extracellular acidification and mitochondrial oxygen consumption and increased expression of proinflammatory cytokines, such as Tnf, Il1b, and Il6. HIV-1 TAT-mediated defective mitophagy leading to microglial activation was further validated in vivo in the brains of HIV-1 transgenic rats. In conclusion, HIV-1 TAT activates microglia by increasing mitochondrial damage via defective mitophagy.ABBREVIATIONS: 3-MA: 3-methyladenine; Δψm: mitochondrial membrane potential; ACTB: actin, beta; AIF1: allograft inflammatory factor 1; ATP: adenosine triphosphate; BAF: bafilomycin A1; BECN1: beclin 1, autophagy related; cART: combined antiretroviral therapy; CNS: central nervous system; DNM1L: dynamin 1 like; DMEM: Dulbecco modified Eagle medium; DAPI: 4,6-diamidino-2-phenylindole‎; ECAR: extracellular acidification rate; FBS: fetal bovine serum; FCCP: trifluoromethoxy carbonylcyanide phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAND: HIV-1-associated neurocognitive disorders; HIV-1 TAT: human immunodeficiency virus-1 transactivator of transcription; IL1B: interleukin 1, beta; IL6: interleukin 6; ITGAM: integrin subunit alpha M; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; mPMs: mouse primary microglial cells; MRC: maximal respiratory capacity; mt-CO1: mitochondrially encoded cytochrome c oxidase; mt-ND6: mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 6; NFKB1: nuclear factor kappa B subunit 1; NLRP3: NLR family pyrin domain containing 3; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TNF: tumor necrosis factor.",
author = "Annadurai Thangaraj and Palsamy Periyasamy and Ke Liao and Bendi, {Venkata Sunil} and Shannon Callen and Gurudutt Pendyala and Shilpa Buch",
year = "2018",
doi = "10.1080/15548627.2018.1476810",
language = "English (US)",
volume = "14",
pages = "1596--1619",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",
number = "9",

}

TY - JOUR

T1 - HIV-1 TAT-mediated microglial activation

T2 - role of mitochondrial dysfunction and defective mitophagy

AU - Thangaraj, Annadurai

AU - Periyasamy, Palsamy

AU - Liao, Ke

AU - Bendi, Venkata Sunil

AU - Callen, Shannon

AU - Pendyala, Gurudutt

AU - Buch, Shilpa

PY - 2018

Y1 - 2018

N2 - While the advent of combination antiretroviral therapy (cART) has dramatically increased the life expectancy of HIV-1 infected individuals, paradoxically, however, the prevalence of HIV-1-associated neurocognitive disorders is on the rise. Based on the premise that the cytotoxic HIV-1 protein, transactivator of transcription (TAT), a known activator of glial cells that is found to persist in the central nervous system (CNS) despite cART, we sought to explore the role of defective mitophagy in HIV-1 TAT-mediated microglial activation. Our results demonstrated that exposure of mouse primary microglia to HIV-1 TAT resulted in cellular activation involving altered mitochondrial membrane potential that was accompanied by accumulation of damaged mitochondria. Exposure of microglia to HIV-1 TAT resulted in increased expression of mitophagy signaling proteins, such as PINK1, PRKN, and DNM1L, with a concomitant increase in the formation of autophagosomes, as evidenced by increased expression of BECN1 and MAP1LC3B-II. Intriguingly, exposure of cells to HIV-1 TAT also resulted in increased expression of SQSTM1, signifying thereby a possible blockade of the mitophagy flux, leading, in turn, to the accumulation of mitophagosomes. Interestingly, HIV-1 TAT-mediated activation of microglia was associated with decreased rate of extracellular acidification and mitochondrial oxygen consumption and increased expression of proinflammatory cytokines, such as Tnf, Il1b, and Il6. HIV-1 TAT-mediated defective mitophagy leading to microglial activation was further validated in vivo in the brains of HIV-1 transgenic rats. In conclusion, HIV-1 TAT activates microglia by increasing mitochondrial damage via defective mitophagy.ABBREVIATIONS: 3-MA: 3-methyladenine; Δψm: mitochondrial membrane potential; ACTB: actin, beta; AIF1: allograft inflammatory factor 1; ATP: adenosine triphosphate; BAF: bafilomycin A1; BECN1: beclin 1, autophagy related; cART: combined antiretroviral therapy; CNS: central nervous system; DNM1L: dynamin 1 like; DMEM: Dulbecco modified Eagle medium; DAPI: 4,6-diamidino-2-phenylindole‎; ECAR: extracellular acidification rate; FBS: fetal bovine serum; FCCP: trifluoromethoxy carbonylcyanide phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAND: HIV-1-associated neurocognitive disorders; HIV-1 TAT: human immunodeficiency virus-1 transactivator of transcription; IL1B: interleukin 1, beta; IL6: interleukin 6; ITGAM: integrin subunit alpha M; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; mPMs: mouse primary microglial cells; MRC: maximal respiratory capacity; mt-CO1: mitochondrially encoded cytochrome c oxidase; mt-ND6: mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 6; NFKB1: nuclear factor kappa B subunit 1; NLRP3: NLR family pyrin domain containing 3; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TNF: tumor necrosis factor.

AB - While the advent of combination antiretroviral therapy (cART) has dramatically increased the life expectancy of HIV-1 infected individuals, paradoxically, however, the prevalence of HIV-1-associated neurocognitive disorders is on the rise. Based on the premise that the cytotoxic HIV-1 protein, transactivator of transcription (TAT), a known activator of glial cells that is found to persist in the central nervous system (CNS) despite cART, we sought to explore the role of defective mitophagy in HIV-1 TAT-mediated microglial activation. Our results demonstrated that exposure of mouse primary microglia to HIV-1 TAT resulted in cellular activation involving altered mitochondrial membrane potential that was accompanied by accumulation of damaged mitochondria. Exposure of microglia to HIV-1 TAT resulted in increased expression of mitophagy signaling proteins, such as PINK1, PRKN, and DNM1L, with a concomitant increase in the formation of autophagosomes, as evidenced by increased expression of BECN1 and MAP1LC3B-II. Intriguingly, exposure of cells to HIV-1 TAT also resulted in increased expression of SQSTM1, signifying thereby a possible blockade of the mitophagy flux, leading, in turn, to the accumulation of mitophagosomes. Interestingly, HIV-1 TAT-mediated activation of microglia was associated with decreased rate of extracellular acidification and mitochondrial oxygen consumption and increased expression of proinflammatory cytokines, such as Tnf, Il1b, and Il6. HIV-1 TAT-mediated defective mitophagy leading to microglial activation was further validated in vivo in the brains of HIV-1 transgenic rats. In conclusion, HIV-1 TAT activates microglia by increasing mitochondrial damage via defective mitophagy.ABBREVIATIONS: 3-MA: 3-methyladenine; Δψm: mitochondrial membrane potential; ACTB: actin, beta; AIF1: allograft inflammatory factor 1; ATP: adenosine triphosphate; BAF: bafilomycin A1; BECN1: beclin 1, autophagy related; cART: combined antiretroviral therapy; CNS: central nervous system; DNM1L: dynamin 1 like; DMEM: Dulbecco modified Eagle medium; DAPI: 4,6-diamidino-2-phenylindole‎; ECAR: extracellular acidification rate; FBS: fetal bovine serum; FCCP: trifluoromethoxy carbonylcyanide phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAND: HIV-1-associated neurocognitive disorders; HIV-1 TAT: human immunodeficiency virus-1 transactivator of transcription; IL1B: interleukin 1, beta; IL6: interleukin 6; ITGAM: integrin subunit alpha M; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; mPMs: mouse primary microglial cells; MRC: maximal respiratory capacity; mt-CO1: mitochondrially encoded cytochrome c oxidase; mt-ND6: mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 6; NFKB1: nuclear factor kappa B subunit 1; NLRP3: NLR family pyrin domain containing 3; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TNF: tumor necrosis factor.

U2 - 10.1080/15548627.2018.1476810

DO - 10.1080/15548627.2018.1476810

M3 - Article

C2 - 29966509

VL - 14

SP - 1596

EP - 1619

JO - Autophagy

JF - Autophagy

SN - 1554-8627

IS - 9

ER -