Inhibition of topoisomerase IIA (Top2α) induces telomeric DNA damage and T cell dysfunction during chronic viral infection

Dang, Xindi; Ogbu, Stella C.; Zhao, Juan; Nguyen, Lam; Cao, Dechao; Khanal, Sushant; Schank, Madison; Thakuri, Bal Krishna Chand; Wu, Xiao Y.; Morrison, Zheng D.; Zhang, Jinyu; Li, Zhengke; Gazzar, Mohamed El; Ning, Shunbin; Wang, Zhengqiang; Moorman, Jonathan P.; Yao, Zhi Q.

doi:10.1038/s41419-020-2395-2

Cited by 22 publications

(37 citation statements)

References 52 publications

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“…Given the known role of telomeric DNA damage in T cell dysfunction during chronic viral infections 14 , 15 , 21 , 36 – 38 , and that only PGC-1α, but not PGC1β, was inhibited by KML001 treatment (Fig. 2C, D ), we examined the frequencies of PGC-1α + cells in CD4 T cell subsets in PLHIV, in which we have recently shown an aging phenotype with shortened telomeres 36 and compromised mitochondria (unpublished observations).…”

Section: Resultsmentioning

confidence: 99%

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Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway

Schank¹,

Zhao²,

Wang³

et al. 2020

Cell Death Dis

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Telomere erosion and mitochondrial dysfunction are prominent features of aging cells with progressive declines of cellular functions. Whether telomere injury induces mitochondrial dysfunction in human T lymphocytes, the major component of adaptive host immunity against infection and malignancy, remains unclear. We have recently shown that disruption of telomere integrity by KML001, a telomere-targeting drug, induces T cell senescence and apoptosis via the telomeric DNA damage response (DDR). In this study, we used KML001 to further investigate the role and mechanism of telomere injury in mitochondrial dysregulation in aging T cells. We demonstrate that targeting telomeres by KML001 induces mitochondrial dysfunction, as evidenced by increased mitochondrial swelling and decreased mitochondrial membrane potential, oxidative phosphorylation, mitochondrial DNA content, mitochondrial respiration, oxygen consumption, glycolysis, and ATP energy production. Mechanistically, we found that the KML001-induced telomeric DDR activated p53 signaling, which in turn repressed the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1), leading to T cell mitochondrial dysfunction. These results, forging a direct link between telomeric and mitochondrial biology, shed new light on the human T cell aging network, and demonstrate that the p53-PGC-1α-NRF-1 axis contributes to mitochondrial dysfunction in the setting of telomeric DDR. This study suggests that targeting this axis may offer an alternative, novel approach to prevent telomere damage-mediated mitochondrial and T cell dysfunctions to combat a wide range of immune aging-associated human diseases.

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Section: Resultsmentioning

confidence: 99%

“…Given the known role of telomeric DNA damage in T cell dysfunction during chronic viral infections 14,15,21,[36][37][38] , Fig. 1 Telomere damage by KML001 impairs mitochondrial functions in human CD4 T cells.…”

Section: Telomere Injury By Kml001 Represses the Pgc-1α Network Govermentioning

confidence: 99%

Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway

Schank¹,

Zhao²,

Wang³

et al. 2020

Cell Death Dis

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“…Notably, GAS5 effects on T cell exhaustion during HIV infection may be mediated by mechanism(s) beyond GAS5-miR21 mediated signaling. Bottom: Deficiencies in Top1/2a, ATM, hTERT, and TRF2 that can cause telomeric DNA damage (30)(31)(32)(33)(34)36) are known to contribute to dysfunctional CD4 T cells in HIV patients.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that PLHIV exhibit CD4 T cell exhaustion, senescence, apoptosis, and dysfunction, despite ostensibly complete control of viral replication by ART (30)(31)(32)(33)(34)(35)(36). How T cell functions are dysregulated in ART-controlled PLHIV is incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV

et al. 2021

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T cells are critical for the control of viral infections and T cell responses are regulated by a dynamic network of non-coding RNAs, including microRNAs (miR) and long non-coding RNAs (lncRNA). Here we show that an activation-induced decline of lncRNA growth arrest-specific transcript 5 (GAS5) activates DNA damage response (DDR), and regulates cellular functions and apoptosis in CD4 T cells derived from people living with HIV (PLHIV) via upregulation of miR-21. Notably, GAS5-miR21-mediated DDR and T cell dysfunction are observed in PLHIV on antiretroviral therapy (ART), who often exhibit immune activation due to low-grade inflammation despite robust virologic control. We found that GAS5 negatively regulates miR-21 expression, which in turn controls critical signaling pathways involved in DNA damage and cellular response. The sustained stimulation of T cells decreased GAS5, increased miR-21 and, as a result, caused dysfunction and apoptosis in CD4 T cells. Importantly, this inflammation-driven T cell over-activation and aberrant apoptosis in ART-controlled PLHIV and healthy subjects (HS) could be reversed by antagonizing the GAS5-miR-21 axis. Also, mutation of the miR-21 binding site on exon 4 of GAS5 gene to generate a GAS5 mutant abolished its ability to regulate miR-21 expression as well as T cell activation and apoptosis markers compared to the wild-type GAS5 transcript. Our data suggest that GAS5 regulates TCR-mediated activation and apoptosis in CD4 T cells during HIV infection through miR-21-mediated signaling. However, GAS5 effects on T cell exhaustion during HIV infection may be mediated by a mechanism beyond the GAS5-miR-21-mediated signaling. These results indicate that targeting the GAS5-miR-21 axis may improve activity and longevity of CD4 T cells in ART-treated PLHIV. This approach may also be useful for targeting other infectious or inflammatory diseases associated with T cell over-activation, exhaustion, and premature immune aging.

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“…Nuclear DNA repair pathways, such as base excision repair and double-strand break repair, can repair damaged mtDNA through nuclear-encoded genes; however, these processes may be deregulated during HIV-infection. For instance, emerging work from our group and others have shown dysregulation of critical DNA damage response proteins, such as ATM, ATR, DNA-PKcs, TOP I/IIα, and p53 in the setting of HIV-infection [ 39 , 43 , 44 , 45 , 46 , 47 , 48 ]. The literature shows that mitochondrial function and signaling pathways become disrupted in the presence of HIV-infection and ART treatment.…”

Section: Introductionmentioning

confidence: 99%

The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging

Schank

Zhao

Moorman

et al. 2021

Cells

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According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with viral persistence, residual inflammation, and metabolic disturbances. Indeed, due to the presence of viral reservoirs, lifelong ART therapy is required to control viremia and prevent disease progression into acquired immune deficiency syndrome (AIDS). Successful ART treatment allows people living with HIV (PLHIV) to achieve a similar life expectancy to uninfected individuals. However, recent studies have illustrated the presence of increased comorbidities, such as accelerated, premature immune aging, in ART-controlled PLHIV compared to uninfected individuals. Studies suggest that both HIV-infection and ART-treatment lead to mitochondrial dysfunction, ultimately resulting in cellular exhaustion, senescence, and apoptosis. Since mitochondria are essential cellular organelles for energy homeostasis and cellular metabolism, their compromise leads to decreased oxidative phosphorylation (OXPHOS), ATP synthesis, gluconeogenesis, and beta-oxidation, abnormal cell homeostasis, increased oxidative stress, depolarization of the mitochondrial membrane potential, and upregulation of mitochondrial DNA mutations and cellular apoptosis. The progressive mitochondrial damage induced by HIV-infection and ART-treatment likely contributes to accelerated aging, senescence, and cellular dysfunction in PLHIV. This review discusses the connections between mitochondrial compromise and cellular dysfunction associated with HIV- and ART-induced toxicities, providing new insights into how HIV and current ART directly impact mitochondrial functions and contribute to cellular senescence and aging in PLHIV. Identifying this nexus and potential mechanisms may be beneficial in developing improved therapeutics for treating PLHIV.

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Inhibition of topoisomerase IIA (Top2α) induces telomeric DNA damage and T cell dysfunction during chronic viral infection

Cited by 22 publications

References 52 publications

Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway

Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway

Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV

The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging

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