Liblova Zuzana, Maurencova Dominika, Salovska Barbora, Kratky Marek, Mracek Tomas, Korandova Zuzana, Pecinova Alena, Vasicova Pavla, Rysanek David, Andera Ladislav, Fabrik Ivo, Kupcik Rudolf, Kashmel Pavel, Sultana Pinky, Tambor Vojtech, Bartek Jiri, Novak Josef, Vajrychova Marie, Hodny Zdenek
Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
Laboratory of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
Mol Oncol. 2025 Sep;19(9):2619-2647. doi: 10.1002/1878-0261.70039. Epub 2025 Apr 27.
Cellular senescence has recently been recognized as a significant contributor to the poor prognosis of glioblastoma, one of the most aggressive brain tumors. Consequently, effectively eliminating senescent glioblastoma cells could benefit patients. Human ADP/ATP translocases (ANTs) play a role in oxidative phosphorylation in both normal and tumor cells. Previous research has shown that the sensitivity of senescent cells to mitochondria-targeted senolytics depends on the level of ANT2. Here, we systematically mapped the transcript and protein levels of ANT isoforms in various types of senescence and glioblastoma tumorigenesis. We employed bioinformatics analysis, targeted mass spectrometry, RT-PCR, immunoblotting, and assessment of cellular energy state to elucidate how individual ANT isoforms are expressed during the development of senescence in noncancerous and glioblastoma cells. We observed a consistent elevation of ANT1 protein levels across all tested senescence types, while ANT2 and ANT3 exhibited variable changes. Alterations in ANT protein isoform levels correlated with shifts in the cellular oxygen consumption rate. Our findings suggest that ANT isoforms are mutually interchangeable for oxidative phosphorylation and manipulating individual ANT isoforms could have potential for senolytic therapy.
细胞衰老最近被认为是胶质母细胞瘤（最具侵袭性的脑肿瘤之一）预后不良的重要因素。因此，有效清除衰老的胶质母细胞瘤细胞可能会使患者受益。人类ADP/ATP转位酶（ANTs）在正常细胞和肿瘤细胞的氧化磷酸化过程中都发挥作用。先前的研究表明，衰老细胞对线粒体靶向衰老药物的敏感性取决于ANT2的水平。在此，我们系统地绘制了各种类型衰老和胶质母细胞瘤肿瘤发生过程中ANT亚型的转录本和蛋白质水平。我们采用生物信息学分析、靶向质谱分析、RT-PCR、免疫印迹以及细胞能量状态评估，以阐明在非癌细胞和胶质母细胞瘤细胞衰老过程中各个ANT亚型是如何表达的。我们观察到在所有测试的衰老类型中，ANT1蛋白水平持续升高，而ANT2和ANT3则表现出不同的变化。ANT蛋白亚型水平的改变与细胞耗氧率的变化相关。我们的研究结果表明，ANT亚型在氧化磷酸化过程中可相互替代，操纵单个ANT亚型可能具有衰老药物治疗的潜力。
