Mitochondrial biogenesis is altered in HIV+ brains exposed to ART: Implications for therapeutic targeting of astroglia.
Anti-HIV Agents
/ pharmacology
Astrocytes
/ drug effects
Brain
/ drug effects
Cells, Cultured
DNA-Binding Proteins
/ metabolism
HIV Seropositivity
/ drug therapy
Humans
Inflammation
/ metabolism
Interleukin-1beta
/ pharmacology
Mitochondria
/ drug effects
Mitochondrial Proteins
/ metabolism
Neurons
/ drug effects
Organelle Biogenesis
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ metabolism
Transcription Factors
/ metabolism
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
19
01
2019
revised:
15
05
2019
accepted:
10
06
2019
pubmed:
27
6
2019
medline:
25
3
2020
entrez:
26
6
2019
Statut:
ppublish
Résumé
The neuropathogenesis of HIV associated neurocognitive disorders (HAND) involves disruption of mitochondrial homeostasis and increased neuroinflammation. However, it is unknown if alterations in mitochondrial biogenesis in the brain underlie the neuropathogenesis of HAND. In this study, neuropathological and molecular analyses of mitochondrial biogenesis and inflammatory pathways were performed in brain specimens from a well-characterized cohort of HIV+ cases that were on antiretroviral regimens. In vitro investigations using primary human astroglia and neurons were used to probe the underlying mechanisms of mitochondrial alterations. In frontal cortices from HAND brains compared to cognitive normal brains, total levels of transcription factors that regulate mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and transcription factor A, mitochondrial (TFAM) were decreased. Immunohistochemical analyses revealed that TFAM was decreased in neurons and increased in astroglia. These changes were accompanied by decreased total mitochondrial DNA per cell and increased levels of messenger RNA for the proinflammatory cytokine interleukin (IL)-1β. To determine how IL-1β affects astroglial bioenergetic processes and mitochondrial activity, human astroglial cultures were exposed to recombinant IL-1β. IL-1β induced mitochondrial activity within 30 min of treatment, altered mitochondrial related gene expression, altered mitochondrial morphology, enhanced adenoside triphosphate (ATP) utilization and increased the expression of inflammatory cytokines. WIN55,212-2 (WIN), an aminoalkylindole derivative and cannabinoid receptor agonist, blocked IL-1β-induced bioenergetic fluctuations and inflammatory gene expression in astroglia independent of cannabinoid receptor (CB)1 and peroxisome proliferator-activated receptor (PPAR) γ. A PPARα antagonist reversed the anti-inflammatory effects of WIN in human astroglia. These results show that mitochondrial biogenesis is differentially regulated in neurons and astroglia in HAND brains and that targeting astroglial bioenergetic processes may be a strategy to modulate neuroinflammation.
Identifiants
pubmed: 31238091
pii: S0969-9961(19)30156-1
doi: 10.1016/j.nbd.2019.104502
pmc: PMC6714553
mid: NIHMS1533939
pii:
doi:
Substances chimiques
Anti-HIV Agents
0
DNA-Binding Proteins
0
Interleukin-1beta
0
Mitochondrial Proteins
0
PPARGC1A protein, human
0
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
0
TFAM protein, human
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
104502Subventions
Organisme : NIMH NIH HHS
ID : U24 MH100929
Pays : United States
Organisme : NIDA NIH HHS
ID : P50 DA026306
Pays : United States
Organisme : NIMH NIH HHS
ID : U24 MH100931
Pays : United States
Organisme : NIMH NIH HHS
ID : U24 MH100928
Pays : United States
Organisme : NINDS NIH HHS
ID : R41 NS105177
Pays : United States
Organisme : NIMH NIH HHS
ID : K01 MH115819
Pays : United States
Organisme : NIMH NIH HHS
ID : P30 MH062512
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH105319
Pays : United States
Organisme : NIMH NIH HHS
ID : U24 MH100925
Pays : United States
Organisme : NIMH NIH HHS
ID : U24 MH100930
Pays : United States
Organisme : NIMHD NIH HHS
ID : L60 MD013161
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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