The role of frataxin in fission yeast iron metabolism: Implications for Friedreich's ataxia

Background

The neurodegenerative disease Friedreich's ataxia is the result of frataxin deficiency. Frataxin is a mitochondrial protein involved in iron–sulfur cluster (Fe–S) cofactor biogenesis, but its functional role in this pathway is debated. This is due to the interconnectivity of iron metabolic and oxidative stress response pathways that make distinguishing primary effects of frataxin deficiency challenging. Since Fe–S cluster assembly is conserved, frataxin overexpression phenotypes in a simple eukaryotic organism will provide additional insight into frataxin function.

Methods

The Schizosaccharomyces pombe frataxin homologue (fxn1) was overexpressed from a plasmid under a thiamine repressible promoter. The S. pombe transformants were characterized at several expression strengths for cellular growth, mitochondrial organization, iron levels, oxidative stress, and activities of Fe–S cluster containing enzymes.

Results

Observed phenotypes were dependent on the amount of Fxn1 overexpression. High Fxn1 overexpression severely inhibited S. pombe growth, impaired mitochondrial membrane integrity and cellular respiration, and led to Fxn1 aggregation. Cellular iron accumulation was observed at moderate Fxn1 overexpression but was most pronounced at high levels of Fxn1. All levels of Fxn1 overexpression up-regulated oxidative stress defense and mitochondrial Fe–S cluster containing enzyme activities.

Conclusions

Despite the presence of oxidative stress and accumulated iron, activation of Fe–S cluster enzymes was common to all levels of Fxn1 overexpression; therefore, Fxn1 may regulate the efficiency of Fe–S cluster biogenesis in S. pombe.

General Significance

We provide evidence that suggests that dysregulated Fe–S cluster biogenesis is a primary effect of both frataxin overexpression and deficiency as in Friedreich's ataxia.     

家兔实验性心肌缺血的定量酶组织化学研究

目的研究心肌缺血后琥珀酸脱氢酶(SDH)、酸性磷酸酶(ACP)及线粒体腺苷三磷酸酶(mitoATPase)的情况,力求寻找一种更为理想的诊断早期心肌缺血的方法.方法结扎家兔左冠状动脉主干建立实验性心肌缺血的动物模型,常规组织学和透射电镜技术观察缺血心肌的组织学和超微结构改变,脱氢酶染色观察大体心肌的缺血情况,并分别采用硝基四氮唑蓝法、硝酸铅法和镁离子激活法研究结扎后0.5、1、2、4、8、12h左室前壁SDH、ACP以及mitoATPase水平的动态变化,显微图像分析系统测定其平均灰度值进行定量分析.结果①缺血后1h SDH活性开始降低,随着缺血时间的延长其表达水平不断下降,在1、2、4、8、12h平均灰度值分别为97.8488±8.13077、105.376±6.06887、112.584±5.18463、124.886±12.1167和144.605±13.9902(P<0.01) ②ACP活性在缺血后4h明显增强,随着缺血时间的延长其表达水平不断增强,缺血后4、8、12h平均灰度值分别为186.494±15.7005、173.158±12.6425和162.506±11.5195(P<0.01)③缺血2h后mitoATPase表达水平显著下降,其强度随着缺血时间的延长不断减低,缺血2、4、8、12h平均灰度值分别为164.153±15.6087、171.256±17.3428、183.518±18.0872和203.218±11.7952(P<0.01).结论 SDH和mitoATPase活性的不断下降及ACP活性的逐渐增强在缺血心肌细胞的演变过程中起着重要作用.     

TET-Mediated Hypermethylation Primes SDH-Deficient Cells for HIF2α-Driven Mesenchymal Transition

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The small members of the JMJD protein family: Enzymatic jewels or jinxes?

Jumonji C domain-containing (JMJD) proteins are mostly epigenetic regulators that demethylate histones. However, a hitherto neglected subfamily of JMJD proteins, evolutionarily distant and characterized by their relatively small molecular weight, exerts different functions by hydroxylating proteins and RNA. Recently, unsuspected proteolytic and tyrosine kinase activities were also ascribed to some of these small JMJD proteins, further increasing their enzymatic versatility. Here, we discuss the ten human small JMJD proteins (HIF1AN, HSPBAP1, JMJD4, JMJD5, JMJD6, JMJD7, JMJD8, RIOX1, RIOX2, TYW5) and their diverse physiological functions. In particular, we focus on the roles of these small JMJD proteins in cancer and other maladies and how they are modulated in diseased cells by an altered metabolic milieu, including hypoxia, reactive oxygen species and oncometabolites. Because small JMJD proteins are enzymes, they are amenable to inhibition by small molecules and may represent novel targets in the therapy of cancer and other diseases.