In Vitro interaction between yeast frataxin and superoxide dismutases: Influence of mitochondrial metals

Han, Thi Hong Lien; Camadro, Jean‐Michel; Barbault, Florent; Santos, Renata; Chahine, Jean‐Michel El Hage; Ha-Duong, Nguyêt-Thanh

doi:10.1016/j.bbagen.2019.02.011

Cited by 6 publications

(8 citation statements)

References 67 publications

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“…This study stemmed from previous work by Han et al [ 29 ], which reported on the interaction between yeast FXN and SODs (bovine and human, in that work). To give full meaning to the results, however, the question of whether the same interaction could be detected between human FXN and human SODs needed to be addressed.…”

Section: Discussionmentioning

confidence: 75%

“…To give full meaning to the results, however, the question of whether the same interaction could be detected between human FXN and human SODs needed to be addressed. In this work, we investigated the interaction between the mature form of FXN and mitochondrial SOD2, since Han and coworkers estimated that at physiological concentrations a complex between FXN and SOD1 could not be formed within the mitochondria [ 29 ]. Furthermore, since SOD1 is primarily a cytosolic protein, it would probably interact with the immature form of FXN.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in the context of the latter function, yeast FXN has been shown to interact with superoxide dismutases (SODs) [ 29 ]. SODs, a ubiquitous class of antioxidant enzymes, play a crucial role in the response to oxidative stress, catalyzing the dismutation of superoxide radicals into molecular oxygen and hydrogen peroxide.…”

Section: Introductionmentioning

confidence: 99%

“…In this work, building on previous in vitro work by Han et al on the interactions between yeast FXN and bovine SOD1 and between yeast FXN and human SOD2 [ 29 ], we focus on the study of human FXN in its mature form (FXN 90–210) and human SOD2. Since human and yeast FXN show a good degree of homology, the interaction is likely to be conserved, and we use human proteins to confirm the interaction and gain a deeper molecular insight into the interface of the complex with a combined in vitro and in silico approach.…”

Section: Introductionmentioning

confidence: 99%

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A Combined Spectroscopic and In Silico Approach to Evaluate the Interaction of Human Frataxin with Mitochondrial Superoxide Dismutase

et al. 2021

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Frataxin (FXN) is a highly conserved mitochondrial protein whose deficiency causes Friedreich’s ataxia, a neurodegenerative disease. The precise physiological function of FXN is still unclear; however, there is experimental evidence that the protein is involved in biosynthetic iron–sulfur cluster machinery, redox imbalance, and iron homeostasis. FXN is synthesized in the cytosol and imported into the mitochondria, where it is proteolytically cleaved to the mature form. Its involvement in the redox imbalance suggests that FXN could interact with mitochondrial superoxide dismutase (SOD2), a key enzyme in antioxidant cellular defense. In this work, we use site-directed spin labelling coupled to electron paramagnetic resonance spectroscopy (SDSL-EPR) and fluorescence quenching experiments to investigate the interaction between human FXN and SOD2 in vitro. Spectroscopic data are combined with rigid body protein–protein docking to assess the potential structure of the FXN-SOD2 complex, which leaves the metal binding region of FXN accessible to the solvent. We provide evidence that human FXN interacts with human SOD2 in vitro and that the complex is in fast exchange. This interaction could be relevant during the assembly of iron-sulfur (FeS) clusters and/or their incorporation in proteins when FeS clusters are potentially susceptible to attacks by reactive oxygen species.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Combined Spectroscopic and In Silico Approach to Evaluate the Interaction of Human Frataxin with Mitochondrial Superoxide Dismutase

et al. 2021

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“…Differently to healthy controls, superoxide dismutases (SODs) are not upregulated in FRDA patients treated with low doses of H2O2 and iron [36]. Moreover, the activities of SODs are notably enhanced upon interaction with Yfh1, which confirms the participation of this frataxin orthologue in the defense against oxidative stress [37]. In addition, frataxin deficiency decreases the total glutathione levels [32], while depleting the aconitase activity and disrupting the mitochondrial Fe-S cluster biogenesis [38].…”

Section: Introductionmentioning

confidence: 88%

Frataxins Emerge as New Players of the Intracellular Antioxidant Machinery

et al. 2021

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Frataxin is a mitochondrial protein which deficiency causes Friedreich’s ataxia, a cardio-neurodegenerative disease. The lack of frataxin induces the dysregulation of mitochondrial iron homeostasis and oxidative stress, which finally causes the neuronal death. The mechanism through which frataxin regulates the oxidative stress balance is rather complex and poorly understood. While the absence of human (Hfra) and yeast (Yfh1) frataxins turn out cells sensitive to oxidative stress, this does not occur when the frataxin gene is knocked-out in E. coli. To better understand the biological roles of Hfra and Yfh1 as endogenous antioxidants, we have studied their ability to inhibit the formation of reactive oxygen species (ROS) from Cu2+- and Fe3+-catalyzed degradation of ascorbic acid. Both proteins drastically reduce the formation of ROS, and during this process they are not oxidized. In addition, we have also demonstrated that merely the presence of Yfh1 or Hfra is enough to protect a highly oxidation-prone protein such as α-synuclein. This unspecific intervention (without a direct binding) suggests that frataxins could act as a shield to prevent the oxidation of a broad set of intracellular proteins, and reinforces that idea that frataxin can be used to prevent neurological pathologies linked to an enhanced oxidative stress.

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