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

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

doi:10.1038/s41419-020-03238-7

Cited by 27 publications

(56 citation statements)

References 51 publications

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“…The model of increased oxidative stress inducing mtDNA mutations is a central mechanism commonly used to explain the aging phenomenon. Furthermore, the expression of critical proteins involved in mitochondrial biogenesis and mtDNA maintenance, including PGC-1α, ERR-α, NRF-1, and TFAM are significantly downregulated in aging cells or tissues [ 144 , 154 , 155 , 156 , 157 ]. Interestingly, age-linked associations have been made across a wide range of chronic viral infections, including but not limited to HIV, HCV, HBV, and CMV, as evidenced by increased telomere erosion and telomeric DNA damage, mitochondrial dysfunction, and cellular senescence [ 43 , 57 , 158 , 159 , 160 ].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…mtDNA and 8-oxoG analyses were performed as described previously ( 24 ). Briefly, genomic DNA was purified from CD4 T cells stimulated with 1ug/ml anti-CD3 and anti-CD28 as described above, and the DNA concentration was measured.…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis was performed as described previously ( 24 ). Primary antibodies included PGC1α (Cat #2178), mtTFA (Cat #8076), ERRα (Cat #13826), NRF-1 (Cat #46743), SOD1 (Cat #4266), GPx1 (Cat #3206), PCK1 (Cat #12940), and G6PD (Cat #12263) (all from Cell Signaling Technology; Danvers, MA), PGC1β (ab176328), PPARα (ab191226), and ACADM (ab110296) (all from Abcam).…”

Section: Methodsmentioning

confidence: 99%

“…Telomere loss and mitochondrial compromise are the two most prominent features of cell aging or senescence. We have previously reported that chronic viral (HIV, HCV) infection can cause premature T cell aging, characterized by overexpression of aging markers and shortened telomeres (23)(24)(25)(26)(27)(28)(29)(30)(31). Since mitochondria are energy powerhouse organelles and their functions are critical for cell activity and survival (32,33), here we analyzed CD4 T cell homeostasis, mitochondrial functions, and regulators of mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) in HIV-INRs, HIV-IRs, and healthy subjects (HS).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Functions Are Compromised in CD4 T Cells From ART-Controlled PLHIV

Zhao

Schank

et al. 2021

Front. Immunol.

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The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs.

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

Cited by 27 publications

References 51 publications

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

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

Mitochondrial Functions Are Compromised in CD4 T Cells From ART-Controlled PLHIV

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

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