癌基因诱导的衰老线粒体代谢和生物能驱动分泌表型：进一步鉴定以及与其他衰老诱导刺激的比较

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology Pub Date : 2025-03-22 DOI:10.1016/j.redox.2025.103606

Inés Marmisolle , Eliana Chacón , Santiago Mansilla , Santiago Ruiz , Mariana Bresque , Jennyfer Martínez , Ricardo Iván Martínez-Zamudio , Utz Herbig , Jie Liu , Toren Finkel , Carlos Escande , Laura Castro , Celia Quijano

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引用次数: 0

摘要

细胞衰老的特征是增殖停滞和衰老相关分泌表型（SASP），在衰老和各种年龄相关疾病的进展中起作用。虽然各种代谢改变已被报道，没有共识存在关于线粒体生物能量学。在这里，我们比较了不同刺激物诱导衰老后人成纤维细胞的线粒体代谢：氧化剂过氧化氢（H2O2）、遗传毒性阿霉素、序列传代或H-RASG12V致癌基因（RAS）的表达。在H2O2、阿霉素或连续传代诱导的衰老中，呼吸控制比（RCR）和偶联效率与对照细胞相比下降。相反，癌基因诱导的衰老细胞在呼吸速率、RCR、备用呼吸量和偶联效率方面总体上有所增加。在癌基因诱导的衰老（OIS）中，呼吸速率的增加伴随着脂肪酸分解代谢的增加、AMPK的激活和持续的DNA损伤反应（DDR），这些都不存在于H2O2或阿霉素诱导的衰老细胞中。抑制AMPK可降低OIS中线粒体耗氧量和促炎细胞因子的分泌。对OIS中参与乙酰辅酶a代谢的酶的评估显示，丙酮酸脱氢酶复合物（PDH）增加3- 7.5倍，线粒体乌头酶抑制40%，atp -柠檬酸裂解酶（ACLY）磷酸化和激活增加，乙酰辅酶a羧化酶（ACC）抑制。去乙酰化酶SIRT6 （SIRT6）的表达和细胞核水平也显著升高。这些变化可以影响乙酰辅酶a的亚细胞分布，并调节细胞质和细胞核中的蛋白质乙酰化反应。事实上，ACLY抑制降低了OIS中组蛋白3乙酰化（H3K9Ac）和SASP成分的分泌。综上所述，我们的数据显示衰老细胞线粒体能量代谢具有明显的异质性，这取决于诱导刺激，揭示了癌基因诱导的衰老细胞的新代谢特征，并确定了AMPK和ACLY作为SASP调节的潜在靶点。

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Oncogene-induced senescence mitochondrial metabolism and bioenergetics drive the secretory phenotype: further characterization and comparison with other senescence-inducing stimuli

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Oncogene-induced senescence mitochondrial metabolism and bioenergetics drive the secretory phenotype: further characterization and comparison with other senescence-inducing stimuli

Cellular senescence is characterized by proliferation arrest and a senescence-associated secretory phenotype (SASP), that plays a role in aging and the progression of various age-related diseases. Although various metabolic alterations have been reported, no consensus exists regarding mitochondrial bioenergetics. Here we compared mitochondrial metabolism of human fibroblasts after inducing senescence with different stimuli: the oxidant hydrogen peroxide (H₂O₂), the genotoxic doxorubicin, serial passage, or expression of the H-RAS^G12V oncogene (RAS).

In senescence induced by H₂O₂, doxorubicin or serial passage a decrease in respiratory control ratio (RCR) and coupling efficiency was noted, in relation to control cells. On the contrary, oncogene-induced senescent cells had an overall increase in respiration rates, RCR, spare respiratory capacity and coupling efficiency. In oncogene-induced senescence (OIS) the increase in respiration rates was accompanied by an increase in fatty acid catabolism, AMPK activation, and a persistent DNA damage response (DDR), that were not present in senescent cells induced by either H₂O₂ or doxorubicin. Inhibition of AMPK reduced mitochondrial oxygen consumption and secretion of proinflammatory cytokines in OIS.

Assessment of enzymes involved in acetyl-CoA metabolism in OIS showed a 3- to 7.5-fold increase in pyruvate dehydrogenase complex (PDH), a 40% inhibition of mitochondrial aconitase, increased phosphorylation and activation of ATP-citrate lyase (ACLY), and inhibition of acetyl-CoA carboxylase (ACC). There was also a significant increase in expression and nuclear levels of the deacetylase sirtuin 6 (SIRT6). These changes can influence the sub-cellular distribution of acetyl-CoA and modulate protein acetylation reactions in the cytoplasm and nuclei. In fact, ACLY inhibition reduced histone 3 acetylation (H3K9Ac) in OIS and secretion of SASP components.

In summary, our data show marked heterogeneity in mitochondrial energy metabolism of senescent cells, depending on the inducing stimulus, reveal new metabolic features of oncogene-induced senescent cells and identify AMPK and ACLY as potential targets for SASP modulation.

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来源期刊

Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-

CiteScore

19.90

自引率

3.50%

发文量

318

审稿时长

25 days

期刊介绍： Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.