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

Abstract

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.

• Authors: Madison Schank, Juan Zhao, Ling Wang, Zhengke Li, Dechao Cao, Lam Nhat Nguyen, Xindi Dang, Sushant Khanal, Lam Ngoc Thao Nguyen, Bal Krishna Chand Thakuri, Stella C Ogbu, Zeyuan Lu, Jinyu Zhang, Xiao Y Wu, Zheng D Morrison, Mohamed El Gazzar, Shunbin Ning, Jonathan P Moorman, Zhi Q Yao
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 12 Pg. 1030 (12 02 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 33268822 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Arsenites
• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Sodium Compounds
• Tumor Suppressor Protein p53
• sodium arsenite

Topics

• Arsenites (toxicity)
• CD4-Positive T-Lymphocytes (drug effects, pathology)
• DNA Damage
• DNA Repair (drug effects, genetics)
• Down-Regulation (genetics)
• Gene Regulatory Networks (drug effects)
• Homeostasis (drug effects)
• Humans
• Mitochondria (drug effects, pathology)
• Organelle Biogenesis
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (metabolism)
• Signal Transduction (drug effects)
• Sodium Compounds (toxicity)
• Telomere (drug effects, pathology)
• Tumor Suppressor Protein p53 (metabolism)
• Up-Regulation (genetics)