Redox sensitive human mitochondrial aconitase and its interaction with frataxin: In vitro and in silico studies confirm that it takes two to tango

Mansilla, Santiago; Pignataro, Florencia; Sastre, Santiago; Castro, Ignacio Hugo; Chiribao, Ma Laura; Robello, Carlos; Zeida, Ari; Santos, Javier; Castro, Laura

doi:10.1016/j.freeradbiomed.2023.01.028

Cited by 8 publications

(4 citation statements)

References 78 publications

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“…However, frataxin’s role was further investigated in 2004, where it was shown to repair inactivated [3Fe-4S] + cluster in aconitase ( Bulteau et al, 2004 ). These findings were reported in various models and found to be an iron-dependent interaction ( Mansilla et al, 2023 ), which further supports the idea that reduced frataxin leads to greater mitochondrial labile iron levels.…”

Section: Oxidative Stress In Frdasupporting

confidence: 84%

“…Frataxin may stimulate the formation of these cofactors ( Tamarit et al, 2016 ), and therefore reduced levels of frataxin may result in increased labile iron. Frataxin’s role in aconitase activity has also been investigated by several groups ( Rötig et al, 1997 ; Bulteau et al, 2004 ; Tamarit et al, 2016 ; Mansilla et al, 2023 ). When cytosolic iron levels are low, cytosolic aconitase is converted into iron-responsive element binding protein (IRE-BP) ( Rötig et al, 1997 ).…”

Section: Oxidative Stress In Frdamentioning

confidence: 99%

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Emerging antioxidant therapies in Friedreich’s ataxia

Edzeamey,

Ramchunder,

Pourzand

et al. 2024

Front. Pharmacol.

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Friedreich’s ataxia (FRDA) is a rare childhood neurologic disorder, affecting 1 in 50,000 Caucasians. The disease is caused by the abnormal expansion of the GAA repeat sequence in intron 1 of the FXN gene, leading to the reduced expression of the mitochondrial protein frataxin. The disease is characterised by progressive neurodegeneration, hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. The reduced expression of frataxin has been suggested to result in the downregulation of endogenous antioxidant defence mechanisms and mitochondrial bioenergetics, and the increase in mitochondrial iron accumulation thereby leading to oxidative stress. The confirmation of oxidative stress as one of the pathological signatures of FRDA led to the search for antioxidants which can be used as therapeutic modality. Based on this observation, antioxidants with different mechanisms of action have been explored for FRDA therapy since the last two decades. In this review, we bring forth all antioxidants which have been investigated for FRDA therapy and have been signed off for clinical trials. We summarise their various target points in FRDA disease pathway, their performances during clinical trials and possible factors which might have accounted for their failure or otherwise during clinical trials. We also discuss the limitation of the studies completed and propose possible strategies for combinatorial therapy of antioxidants to generate synergistic effect in FRDA patients.

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Section: Oxidative Stress In Frdasupporting

confidence: 84%

Section: Oxidative Stress In Frdamentioning

confidence: 99%

Emerging antioxidant therapies in Friedreich’s ataxia

Edzeamey,

Ramchunder,

Pourzand

et al. 2024

Front. Pharmacol.

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“…The lower expression of ACO in control IFM was consistent with the very low activity values described above. The remaining difference between activity and protein content could be related to the fact that ACO is a redox sensor and very sensitive to ROS ( 54 ). In addition, the ACO reaction exhibits a long lag phase before it reaches a steady state.…”

Section: Discussionmentioning

confidence: 99%

Hyperbaric oxygen treatment reveals spatiotemporal OXPHOS plasticity in the porcine heart

Heidler,

Cabrera-Orefice,

Wittig

et al. 2024

PNAS Nexus

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Cardiomyocytes meet their high ATP demand almost exclusively by oxidative phosphorylation (OXPHOS). Adequate oxygen supply is thus an essential prerequisite to keep OXPHOS operational. At least two spatially distinct mitochondrial subpopulations facilitate OXPHOS in cardiomyocytes, i.e., subsarcolemmal (SSM) and interfibrillar mitochondria (IFM). Their intracellular localization below the sarcolemma or buried deep between the sarcomeres suggests different oxygen availability. Here, we studied SSM and IFM isolated from piglet hearts and found significantly lower activities of electron transport chain (ETC) enzymes and F1FO-ATP synthase in IFM, indicative for compromised energy metabolism. To test the contribution of oxygen availability to this outcome, we ventilated piglets under hyperbaric hyperoxic (HBO) conditions for 240 minutes. HBO treatment raised OXPHOS enzyme activities in IFM to the level of SSM. Complexome profiling analysis revealed that a high proportion of the F1FO-ATP synthase in the IFM was in a disassembled state prior to the HBO treatment. Upon increased oxygen availability, the enzyme was found to be largely assembled, which may account for the observed increase in OXPHOS complex activities. Although HBO also induced transcription of genes involved in mitochondrial biogenesis, a full proteome analysis revealed only minimal alterations, meaning that HBO-mediated tissue remodeling is an unlikely cause for the observed differences in OXPHOS. We conclude that a previously unrecognized oxygen-regulated mechanism may endow cardiac OXPHOS with spatiotemporal plasticity that underlies the enormous metabolic and contractile adaptability of the heart.

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“…Aconitase together with frataxin forms a [4Fe-4S] 2+ cluster as the redox sensor interacts with plenty of reactive oxygen radicals, including H 2 O 2 , ONOO − , and O 2 − , turning mitochondrial [4Fe-4S] 2+ into the [3Fe-4S] + cluster during aging or mitochondrial dysfunction [63]. α-KG dehydrogenase and pyruvate dehydrogenase account for a large amount of H 2 O 2 production in mitochondria.…”

Section: The Tca Cycle Regulates Redox Homeostasismentioning

confidence: 99%

Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease

Lian,

Wu,

Lin

et al. 2024

Antioxidants

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Imbalanced osteogenic cell-mediated bone gain and osteoclastic remodeling accelerates the development of osteoporosis, which is the leading risk factor of disability in the elderly. Harmonizing the metabolic actions of bone-making cells and bone resorbing cells to the mineralized matrix network is required to maintain bone mass homeostasis. The tricarboxylic acid (TCA) cycle in mitochondria is a crucial process for cellular energy production and redox homeostasis. The canonical actions of TCA cycle enzymes and intermediates are indispensable in oxidative phosphorylation and adenosine triphosphate (ATP) biosynthesis for osteogenic differentiation and osteoclast formation. Knockout mouse models identify these enzymes’ roles in bone mass and microarchitecture. In the noncanonical processes, the metabolites as a co-factor or a substrate involve epigenetic modification, including histone acetyltransferases, DNA demethylases, RNA m6A demethylases, and histone demethylases, which affect genomic stability or chromatin accessibility for cell metabolism and bone formation and resorption. The genetic manipulation of these epigenetic regulators or TCA cycle intermediate supplementation compromises age, estrogen deficiency, or inflammation-induced bone mass loss and microstructure deterioration. This review sheds light on the metabolic functions of the TCA cycle in terms of bone integrity and highlights the crosstalk of the TCA cycle and redox and epigenetic pathways in skeletal tissue metabolism and the intermediates as treatment options for delaying osteoporosis.

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Redox sensitive human mitochondrial aconitase and its interaction with frataxin: In vitro and in silico studies confirm that it takes two to tango

Cited by 8 publications

References 78 publications

Emerging antioxidant therapies in Friedreich’s ataxia

Emerging antioxidant therapies in Friedreich’s ataxia

Hyperbaric oxygen treatment reveals spatiotemporal OXPHOS plasticity in the porcine heart

Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease

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