Iron overload alters the energy metabolism in patients with myelodysplastic syndromes: results from the multicenter FISM BIOFER study
Iron overload alters the energy metabolism in patients with myelodysplastic syndromes: results from the multicenter FISM BIOFER study
复制标题
铁超载改变骨髓增生异常综合征患者的能量代谢：来自多中心FISM BIOFER研究的结果
DOI：
10.1038/s41598-020-66162-y
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发表时间：
2020-06-08
影响因子：
4.6
通讯作者：
Frassoni, Francesco
中科院分区：
文献类型：
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作者：
Cilloni, Daniela;Ravera, Silvia;Frassoni, Francesco
骨髓增生异常综合征(MDS)是一种以无效造血和骨髓细胞凋亡增加为特征的血液系统恶性肿瘤，可导致外周血细胞减少。线粒体是细胞凋亡的关键调节者，也是铁积累的场所，有利于产生活性氧物种(ROS)，从而对细胞生存产生不利影响。虽然能量代谢可以代表一个有吸引力的治疗靶点，但它在MDS中的研究很少。这项研究的目的是分析骨髓增生性造血、铁超载和螯合对线粒体代谢的影响。我们比较了38例MDS患者和79例健康对照单个核细胞(MNC)的能量平衡、OxPhos活性和效率、乳酸脱氢酶活性和脂质过氧化作用。我们的数据显示，在衰老过程中，ATP/AMP比率降低，在MDS中甚至更严重，这是由于与脂质过氧化增加相关的OxPhos活性降低所致。此外，在MDS和老年受试者中观察到乳酸发酵的增强，可能是为了恢复能量平衡。体外铁络合可部分恢复MDS患者单核细胞的生化改变，而在年龄匹配的对照样本中仅观察到轻微的影响。相比之下，在年轻健康受试者的单核细胞上添加铁络合剂后，OxPhos的效率降低，乳酸发酵和脂质过氧化增加。综上所述，由于铁的积累，MDS-MNC表现出与氧化应激增加相关的能量代谢改变。这种情况可以通过铁络合部分恢复。
Myelodysplastic syndromes (MDS) are hematological malignancies characterized by ineffective hematopoiesis and increased apoptosis in the bone marrow, which cause peripheral cytopenia. Mitochondria are key regulators of apoptosis and a site of iron accumulation that favors reactive oxygen species (ROS) production with detrimental effects on cell survival. Although the energy metabolism could represent an attractive therapeutic target, it was poorly investigated in MDS. The purpose of the study was to analyze how the presence of myelodysplastic hematopoiesis, iron overload and chelation impact on mitochondrial metabolism. We compared energy balance, OxPhos activity and efficiency, lactic dehydrogenase activity and lipid peroxidation in mononuclear cells (MNCs), isolated from 38 MDS patients and 79 healthy controls. Our data show that ATP/AMP ratio is reduced during aging and even more in MDS due to a decreased OxPhos activity associated with an increment of lipid peroxidation. Moreover, the lactate fermentation enhancement was observed in MDS and elderly subjects, probably as an attempt to restore the energy balance. The biochemical alterations of MNCs from MDS patients have been partially restored by the in vitro iron chelation, while only slight effects were observed in the age-matched control samples. By contrast, the addition of iron chelators on MNCs from young healthy subjects determined a decrement in the OxPhos efficiency and an increment of lactate fermentation and lipid peroxidation. In summary, MDS-MNCs display an altered energy metabolism associated with increased oxidative stress, due to iron accumulation. This condition could be partially restored by iron chelation.