The mitochondrial poison carbonyl cyanide 3-chlorophenyl hydrazone (CCCP) induces aneugenic effects in primary human fibroblasts: a possible link between mitochondrial dysfunction and chromosomal loss.

IF 2.5 4区 医学 Q3 GENETICS & HEREDITY Mutagenesis Pub Date : 2022-04-20 DOI:10.1093/mutage/geac008
F. Marcon, Francesca De Battistis, E. Siniscalchi, R. Crebelli, R. Meschini
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Abstract

An association between proper chromosome segregation and intact mitochondria has been extensively reported. This could be related to the effects on the progression of cell division of altered energy production, increased oxidative stress, and deregulated calcium homeostasis. However, evidence for a direct relationship is still lacking. The present study was aimed at investigating the possible effect of mitochondrial dysfunction on chromosomal instability as detected in primary human cells treated with the mitochondrial poison carbonyl cyanide 3-chlorophenyl hydrazone (CCCP). Chromosome instability was analyzed in anaphase and interphase cells to follow the fate of chromosome damage during the progression of mitosis and the subsequent cell cycle. Through the combination of cytogenetic approaches and molecular analyses, i.e. morphological cell analysis, formation and characterization of micronucleus content, Comet assay, and gene expression, it was demonstrated that the prevalent DNA damage associated with CCCP treatment was the induction of chromosome loss, while primary DNA damage was not detected. No alterations in the shape of anaphase cells were observed nor induction of multipolar spindles. The proper activation of mitotic checkpoint was maintained. A linear dose-response curve characterizing the CCCP effects suggested that multiple cellular targets could be affected by the CCCP-induced mitochondrial dysfunctions triggering aneuploidy. Conversely, a steep increase was induced by the positive control vinblastine, known to have tubulin as a unique target. In addition, the effect of CCCP on mitochondrial function was demonstrated by changes in mitochondrial DNA copy number and in the expression of genes involved in mitochondrial maintenance. Overall, these results indicate that the mitochondrial poison CCCP may induce aneugenic effects.
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线粒体毒性羰基氰化物3-氯苯基腙(CCCP)在原代人成纤维细胞中诱导非优生效应:线粒体功能障碍与染色体丢失之间的可能联系。
正确的染色体分离和完整的线粒体之间的关系已被广泛报道。这可能与能量产生改变、氧化应激增加和钙稳态失调对细胞分裂进程的影响有关。然而,直接关系的证据仍然缺乏。本研究旨在探讨线粒体功能障碍对线粒体毒性羰基氰化3-氯苯基腙(CCCP)处理的人原代细胞染色体不稳定性的可能影响。染色体不稳定性分析在细胞的后期和间期,以跟踪染色体损伤的命运在有丝分裂的进程和随后的细胞周期。通过细胞遗传学方法和分子分析相结合,即形态学细胞分析,微核含量的形成和表征,彗星试验和基因表达,证明了CCCP处理相关的普遍DNA损伤是诱导染色体丢失,而未检测到原发性DNA损伤。未观察到后期细胞形状的改变,也未观察到多极纺锤体的诱导。有丝分裂检查点的正常激活得以维持。表征CCCP效应的线性剂量-反应曲线表明,CCCP诱导的线粒体功能障碍可能会影响多个细胞靶点,从而引发非整倍体。相反,阳性对照长春花碱(已知以微管蛋白为独特靶点)诱导了急剧增加。此外,CCCP对线粒体功能的影响通过改变线粒体DNA拷贝数和参与线粒体维持的基因表达得到证实。总之,这些结果表明线粒体毒性CCCP可能引起非优生效应。
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来源期刊
Mutagenesis
Mutagenesis 生物-毒理学
CiteScore
5.90
自引率
3.70%
发文量
22
审稿时长
6-12 weeks
期刊介绍: Mutagenesis is an international multi-disciplinary journal designed to bring together research aimed at the identification, characterization and elucidation of the mechanisms of action of physical, chemical and biological agents capable of producing genetic change in living organisms and the study of the consequences of such changes.
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