Department of Experimental Medicine, University of Genoa, Via De Toni 14, 16132 Genova, Italy.
CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", Unit of Bologna, Via di Barbiano 1/10, 40136 Bologna, Italy.
Int J Mol Sci. 2023 Mar 31;24(7):6557. doi: 10.3390/ijms24076557.
Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure and aplastic anemia. So far, 23 genes are involved in this pathology, and their mutations lead to a defect in DNA repair. In recent years, it has been observed that FA cells also display mitochondrial metabolism defects, causing an accumulation of intracellular lipids and oxidative damage. However, the molecular mechanisms involved in the metabolic alterations have not yet been elucidated. In this work, by using lymphoblasts and fibroblasts mutated for the gene, oxidative phosphorylation (OxPhos) and mitochondria dynamics markers expression was analyzed. Results show that the metabolic defect does not depend on an altered expression of the proteins involved in OxPhos. However, FA cells are characterized by increased uncoupling protein UCP2 expression. mutation is also associated with DRP1 overexpression that causes an imbalance in the mitochondrial dynamic toward fission and lower expression of Parkin and Beclin1. Treatment with P110, a specific inhibitor of DRP1, shows a partial mitochondrial function recovery and the decrement of DRP1 and UCP2 expression, suggesting a pivotal role of the mitochondrial dynamics in the etiopathology of Fanconi anemia.
范可尼贫血症（FA）是一种罕见的遗传性疾病，其特征是骨髓衰竭和再生障碍性贫血。到目前为止，已有 23 个基因参与了这一病理过程，其突变导致 DNA 修复缺陷。近年来，人们观察到 FA 细胞还存在线粒体代谢缺陷，导致细胞内脂质积累和氧化损伤。然而，涉及代谢改变的分子机制尚未阐明。在这项工作中，通过使用突变的基因的淋巴母细胞和成纤维细胞，分析了氧化磷酸化（OxPhos）和线粒体动力学标记物的表达。结果表明，代谢缺陷不依赖于 OxPhos 相关蛋白表达的改变。然而，FA 细胞的特征是解偶联蛋白 UCP2 的表达增加。 突变也与 DRP1 的过表达相关，导致线粒体动力学向分裂失衡和 Parkin 和 Beclin1 的表达降低。用 P110（DRP1 的特异性抑制剂）治疗显示出部分线粒体功能的恢复和 DRP1 和 UCP2 的表达减少，提示线粒体动力学在范可尼贫血症的发病机制中起着关键作用。
