HIV-1 gp120-Induced Endolysosome de-Acidification Leads to Efflux of Endolysosome Iron, and Increases in Mitochondrial Iron and Reactive Oxygen Species

Halcrow, Peter W.; Lakpa, Koffi L.; Khan, Nabab; Afghah, Zahra; Miller, Nicole; Datta, Gaurav; Chen, Xuesong; Geiger, Jonathan D.

doi:10.1007/s11481-021-09995-2

Cited by 25 publications

(39 citation statements)

References 88 publications

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“…An increase in NOX5 activity and the resulting ROS increase has been shown to take place after gp120 treatment ( Smith et al, 2021 ). This increase in ROS has been linked to gp120 induction of endolysosome de-acidification, which results in increased mitochondrial iron content and directly contributes to the accumulation of cellular ROS ( Halcrow et al, 2021 ). Increased ROS plays a critical role in the formation and accumulation of AGEs.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Allen

Arjona

Santerre

et al. 2022

Front. Cell. Neurosci.

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A significant number of patients infected with HIV-1 suffer from HIV-associated neurocognitive disorders (HAND) such as spatial memory impairments and learning disabilities (SMI-LD). SMI-LD is also observed in patients using combination antiretroviral therapy (cART). Our lab has demonstrated that the HIV-1 protein, gp120, promotes SMI-LD by altering mitochondrial functions and energy production. We have investigated cellular processes upstream of the mitochondrial functions and discovered that gp120 causes metabolic reprogramming. Effectively, the addition of gp120 protein to neuronal cells disrupted the glycolysis pathway at the pyruvate level. Looking for the players involved, we found that gp120 promotes increased expression of polypyrimidine tract binding protein 1 (PTBP1), causing the splicing of pyruvate kinase M (PKM) into PKM1 and PKM2. We have also shown that these events lead to the accumulation of advanced glycation end products (AGEs) and prevent the cleavage of pro-brain-derived neurotrophic factor (pro-BDNF) protein into mature brain-derived neurotrophic factor (BDNF). The accumulation of proBDNF results in signaling that increases the expression of the inducible cAMP early repressor (ICER) protein which then occupies the cAMP response element (CRE)-binding sites within the BDNF promoters II and IV, thus altering normal synaptic plasticity. We reversed these events by adding Tepp-46, which stabilizes the tetrameric form of PKM2. Therefore, we concluded that gp120 reprograms cellular metabolism, causing changes linked to disrupted memory in HIV-infected patients and that preventing the disruption of the metabolism presents a potential cure against HAND progression.

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Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Allen

Arjona

Santerre

et al. 2022

Front. Cell. Neurosci.

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“…Interestingly, impaired endolysosomal acidification, a hallmark of aging (Colacurcio and Nixon, 2016), has been recently associated with iron dyshomeostasis and neuroinflammation in vivo (Halcrow et al, 2021). Pharmacological or genetic-targeting of the vacuolar (v)-ATPase, which that maintains the acidic pH inside the lysosomes, results in functional iron deficiency in both the cytoplasm and the mitochondria.…”

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confidence: 99%

Iron, the endolysosomal system and neuroinflammation: a matter of balance

2022

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“…However, less attention has been paid so far to investigate the potential of directly targeting the lysosomes of MSCs with small molecules, peptide drugs, and nanomaterials. Vacuolar H + -ATPase (v-ATPase) defects are the underlying cause of several human diseases (Haggie and Verkman, 2009;Halcrow et al, 2021). New studies have shown v-ATPase activity is altered, and lysosomal pH regulation is dysregulated during cellular senescence and apoptosis (Nilsson et al, 2006).…”

Section: Preventing Lysosomal Acidification Dysfunction and Senescenc...mentioning

confidence: 99%

Role of Lysosomal Acidification Dysfunction in Mesenchymal Stem Cell Senescence

Zhang

Bai

Hang

et al. 2022

Front. Cell Dev. Biol.

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Mesenchymal stem cell (MSC) transplantation has been widely used as a potential treatment for a variety of diseases. However, the contradiction between the low survival rate of transplanted cells and the beneficial therapeutic effects has affected its clinical use. Lysosomes as organelles at the center of cellular recycling and metabolic signaling, play essential roles in MSC homeostasis. In the first part of this review, we summarize the role of lysosomal acidification dysfunction in MSC senescence. In the second part, we summarize some of the potential strategies targeting lysosomal proteins to enhance the therapeutic effect of MSCs.

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HIV-1 gp120-Induced Endolysosome de-Acidification Leads to Efflux of Endolysosome Iron, and Increases in Mitochondrial Iron and Reactive Oxygen Species

Cited by 25 publications

References 88 publications

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Iron, the endolysosomal system and neuroinflammation: a matter of balance

Role of Lysosomal Acidification Dysfunction in Mesenchymal Stem Cell Senescence

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