Details

Autor(en) / Beteiligte

• Swinton, Mary K.
• Carson, Aliyah
• Telese, Francesca
• Sanchez, Ana B.
• Soontornniyomkij, Benchawanna
• Rad, Leila
• Batki, Isabella
• Quintanilla, Brandi
• Pérez-Santiago, Josué
• Achim, Cristian L.
• Letendre, Scott
• Ellis, Ronald J.
• Grant, Igor
• Murphy, Anne N.
• Fields, Jerel Adam

Titel

Mitochondrial biogenesis is altered in HIV+ brains exposed to ART: Implications for therapeutic targeting of astroglia

Ist Teil von

• Neurobiology of disease, 2019-10, Vol.130, p.104502-104502, Article 104502

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Mitochondrial biogenesis is reduced in brains of HIV+ cases with neurocognitive impairment compared to controls from cART era•TFAM colocalization with neurons is reduced but increased with astroglia in HIV+ brains with neurocognitive impairment•IL-1β increases PGC-1α expression, oxygen consumption rate and extracellular acidification rate in human astroglia•An aminoalkylindole derivative, WIN 55-212-2, blocks IL-1β-induced oxygen consumption and glycolysis in astroglia•WIN 55-212-2 blockage of IL-1β-induced inflammatory gene expression in human astroglia is dependent upon PPARα