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

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

doi:10.1016/j.nbd.2019.104502

Cited by 38 publications

(57 citation statements)

References 83 publications

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“…In support to our study a recent report demonstrated that mitochondrial biogenesis is differentially regulated in neurons and astroglia in HIV associated neurocognitive disorders (HAND) brains and that targeting astroglial bioenergetics processes [64]. Taken together, these data indicate that PGC-1α plays a crucial role in linking stimuli such as HIV infection and cocaine abuse to an internal metabolic response like mitochondrial biogenesis via, among others, the NRF transcription factors.…”

Section: Discussionsupporting

confidence: 91%

HIV-Tat and Cocaine Impact Brain Energy Metabolism: Redox Modification and Mitochondrial Biogenesis Influence NRF-Transcriptional Mediated Neurodegeneration

Sivalingam

Cirino

McLaughlin

et al. 2020

Preprint

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Abstract HIV infection and drugs of abuse induce oxidative stress and redox imbalance, which cause neurodegeneration. The mechanisms by which HIV infection and cocaine consumption affect astrocytes energy metabolism lead neurodegenerative dysfunction remain poorly understood. We investigated how oxidative injury cause energy resource and depletion of glutathione synthetase (GSS), activating energy sensor AMPK-mediated glycolytic enzymes, and mitochondrial biogenesis lead to NRF transcription factors in astrocytes. Both human primary astrocytes in vitro (HIV-1Tat/cocaine) and HIV-inducible Tat (iTat) mice exposed to cocaine inhibit the GSS and altered superoxide dismutase (SOD) level. This, in turn, significantly activated AMPK and raised the several glycolytic enzymes, oxidative phosphorylation, mitochondrial biogenesis of PGC-1α and TFAM, Nrf1 and Nrf2 gene transcription, and protein expression. These results suggest that redox inhibition of GSS altered AMPK activation and mitochondrial biogenesis influence Nrf transcriptions, which are important resource of astrocytes signaling network in brain energy metabolism in HIV-positive cocaine users. In conclusion, HIV-1 Tat altered redox inhibition, thus raising glycolytic metabolic profiles and mitochondrial biogenesis led to Nrf transcription, which impact astrocyte-energy resource and metabolism. Further cocaine comorbidity exacerbation of these effects led to worse in neurodegeneration.

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Section: Discussionsupporting

confidence: 91%

HIV-Tat and Cocaine Impact Brain Energy Metabolism: Redox Modification and Mitochondrial Biogenesis Influence NRF-Transcriptional Mediated Neurodegeneration

Sivalingam

Cirino

McLaughlin

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The current study extends these findings by identifying transcriptional deregulation in MND, specifically C/EBPβ and linking its targets to marker genes in astroglia. This may be particularly important as astroglia have been recently implicated in metabolic complications of HAND and AD [48][49][50][51][52][53]. Also consistent with the findings presented here, a recent study showed that YKL-40, a biomarker that reflects astroglial activation, is upregulated in cerebrospinal fluid from HAD cases and is associated with axonal injury [54].…”

Section: Discussionsupporting

confidence: 88%

Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorders

Canchi

Swinton

Rissman

et al. 2020

Preprint

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Background: HIV-associated neurocognitive disorders (HAND) persist in the era of combined antiretroviral therapy (ART) despite reductions in viral load (VL) and overall disease severity. The mechanisms underlying HAND in ART era are not well understood but are likely multifactorial, involving alterations in common pathways such as inflammation, autophagy, neurogenesis, and mitochondrial function. Newly developed omics approaches hold potential to identify mechanisms driving neuropathogenesis of HIV in the ART era. Methods: In this study, using 33 postmortem frontal cortex (FC) tissues, neuropathological, molecular, and biochemical analyses were used to determine cellular localization and validate expression levels of the prolific transcription factor (TF), CCAAT enhancer binding protein (C/EBP) ß, in brain tissues from HIV+ cognitively normal and HAND cases. RNA sequencing (seq) and transcriptomics analyses were performed on FC tissues including 24 specimens from well-characterized people with HIV that had undergone neurocognitive assessments. In vitro models for brain cells were used to investigate the role of C/EBPß in mediating gene expression. Results: The most robust signal for TF dysregulation was observed in cases diagnosed with Minor Neurocognitive Disorders (MND) compared to cognitive normal (CN) cases. Of particular interest, due to its role in inflammation, autophagy and neurogenesis, C/EBPß was significantly upregulated in MND compared to CN brains. C/EBPß was increased at the protein level in HAND brains. C/EBPß levels were significantly reduced in neurons and increased in astroglia in HAND brains compared to CN. Transfection of human astroglial cells with a plasmid expressing C/EBPß induced expression of multiple targets identified in the transcriptomic analysis of HAND brains, including dynamin-1-like protein (DNM1L) and interleukin-1 receptor-associated kinase 1. Recombinant HIV-Tat reduced and increased C/EBPß levels in neuronal and astroglial cells, respectively. Conclusions: These findings are the first to present RNAseq-based transcriptomic analyses of HIV+ brain tissues, providing further evidence of altered neuroinflammation, neurogenesis, mitochondrial function, and autophagy in HAND. Interestingly, these studies confirm a role for CEBPß in regulating inflammation, metabolism, and autophagy in astroglia. Therapeutic strategies aimed at transcriptional regulation of astroglia or downstream pathways may provide relief to HIV+ patients at risk for HAND and other neurological disorders.

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“…The current study extends these findings by identifying transcriptional deregulation in MND, specifically C/EBPβ and linking its targets to marker genes in astroglia. This may be particularly important as astroglia have been recently implicated in metabolic complications of HAND and AD [49][50][51][52][53][54]. Also, consistent with the findings presented here, a recent study showed that YKL-40, a biomarker that reflects astroglial activation, is upregulated in cerebrospinal fluid from HAD cases and is associated with axonal injury [39].…”

Section: Discussionsupporting

confidence: 87%

Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorder

Canchi

Swinton

Rissman

et al. 2020

J Neuroinflammation

Self Cite

View full text Add to dashboard Cite

Background: HIV-associated neurocognitive disorders (HAND) persist in the era of combined antiretroviral therapy (ART) despite reductions in viral load (VL) and overall disease severity. The mechanisms underlying HAND in the ART era are not well understood but are likely multifactorial, involving alterations in common pathways such as inflammation, autophagy, neurogenesis, and mitochondrial function. Newly developed omics approaches hold potential to identify mechanisms driving neuropathogenesis of HIV in the ART era. Methods: In this study, using 33 postmortem frontal cortex (FC) tissues, neuropathological, molecular, and biochemical analyses were used to determine cellular localization and validate expression levels of the prolific transcription factor (TF), CCAAT enhancer binding protein (C/EBP) β, in brain tissues from HIV+ cognitively normal and HAND cases. RNA sequencing (seq) and transcriptomic analyses were performed on FC tissues including 24 specimens from wellcharacterized people with HIV that had undergone neurocognitive assessments. In vitro models for brain cells were used to investigate the role of C/EBPβ in mediating gene expression.Results: The most robust signal for TF dysregulation was observed in cases diagnosed with minor neurocognitive disorder (MND) compared to cognitive normal (CN) cases. Of particular interest, due to its role in inflammation, autophagy and neurogenesis, C/EBPβ was significantly upregulated in MND compared to CN brains. C/EBPβ was increased at the protein level in HAND brains. C/EBPβ levels were significantly reduced in neurons and increased in astroglia in HAND brains compared to CN. Transfection of human astroglial cells with a plasmid expressing C/ EBPβ induced expression of multiple targets identified in the transcriptomic analysis of HAND brains, including dynamin-1-like protein (DNM1L) and interleukin-1 receptor-associated kinase 1. Recombinant HIV-Tat reduced and increased C/EBPβ levels in neuronal and astroglial cells, respectively.(Continued on next page) Conclusions: These findings are the first to present RNAseq-based transcriptomic analyses of HIV+ brain tissues, providing further evidence of altered neuroinflammation, neurogenesis, mitochondrial function, and autophagy in HAND. Interestingly, these studies confirm a role for CEBPβ in regulating inflammation, metabolism, and autophagy in astroglia. Therapeutic strategies aimed at transcriptional regulation of astroglia or downstream pathways may provide relief to HIV+ patients at risk for HAND and other neurological disorders.

show abstract

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

Cited by 38 publications

References 83 publications

HIV-Tat and Cocaine Impact Brain Energy Metabolism: Redox Modification and Mitochondrial Biogenesis Influence NRF-Transcriptional Mediated Neurodegeneration

HIV-Tat and Cocaine Impact Brain Energy Metabolism: Redox Modification and Mitochondrial Biogenesis Influence NRF-Transcriptional Mediated Neurodegeneration

Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorders

Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorder

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