Iron(II) induces changes in the conformation of mammalian mitochondrial DNA resulting in a reduction of its transcriptional rate

Asín, J. A. Casas; Pérez‐Martos, Acisclo; Fernández‐Silva, Patricio; Montoya, Julio; Andreu, Antoni L.

doi:10.1016/s0014-5793(00)01768-3

Cited by 11 publications

(4 citation statements)

References 26 publications

(28 reference statements)

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“…supercoiled, relaxed circular and linear forms, early studies identified that the supercoiled mtDNA is susceptible to oxidative damage (24–28). Recent evidence suggests that disruption of the supercoiled structure is associated with functional changes in animal mitochondria (29,30). Thus, the structural integrity of mtDNA may serve as a functionally relevant DNA marker to oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

DNA supercoiling suppresses real-time PCR: a new approach to the quantification of mitochondrial DNA damage and repair

Chen¹,

Kadlubar²,

Chen³

2007

Nucleic Acids Research

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As a gold standard for quantification of starting amounts of nucleic acids, real-time PCR is increasingly used in quantitative analysis of mtDNA copy number in medical research. Using supercoiled plasmid DNA and mtDNA modified both in vitro and in cancer cells, we demonstrated that conformational changes in supercoiled DNA have profound influence on real-time PCR quantification. We showed that real-time PCR signal is a positive function of the relaxed forms (open circular and/or linear) rather than the supercoiled form of DNA, and that the conformation transitions mediated by DNA strand breaks are the main basis for sensitive detection of the relaxed DNA. This new finding was then used for sensitive detection of structure-mediated mtDNA damage and repair in stressed cancer cells, and for accurate quantification of total mtDNA copy number when all supercoiled DNA is converted into the relaxed forms using a prior heat-denaturation step. The new approach revealed a dynamic mtDNA response to oxidative stress in prostate cancer cells, which involves not only early structural damage and repair but also sustained copy number reduction induced by hydrogen peroxide. Finally, the supercoiling effect should raise caution in any DNA quantification using real-time PCR.

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Section: Introductionmentioning

confidence: 99%

DNA supercoiling suppresses real-time PCR: a new approach to the quantification of mitochondrial DNA damage and repair

Chen¹,

Kadlubar²,

Chen³

2007

Nucleic Acids Research

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“…Mitochondria play a key role in iron metabolism in which they synthesize heme, assemble iron–sulfur (Fe/S) proteins and participate in cellular iron regulation [68]. Iron is directly involved in several complexes of the mtETC, containing Fe/S clusters (complexes I, II, III and IV) and heme (complexes II, III and IV), enabling oxidative phosphorylation by ATP synthase within the mitochondria [69], but iron is also a critical component of many other heme‐containing enzymes involved in energy production [70]. Activity of mitochondrial complexes I–III, which predominantly contain Fe/S clusters, was shown to be adversely affected by deferoxamine (DFO) treatment, while the exclusively heme‐based complexes IV and V showed unaltered activity (Hoes et al.…”

Section: Ironmentioning

confidence: 99%

Micronutrient deficiencies in heart failure: Mitochondrial dysfunction as a common pathophysiological mechanism?

et al. 2022

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Heart failure is a devastating clinical syndrome, but current therapies are unable to abolish the disease burden. New strategies to treat or prevent heart failure are urgently needed. Over the past decades, a clear relationship has been established between poor cardiac performance and metabolic perturbations, including deficits in substrate uptake and utilization, reduction in mitochondrial oxidative phosphorylation and excessive reactive oxygen species production. Together, these perturbations result in progressive depletion of cardiac adenosine triphosphate (ATP) and cardiac energy deprivation. Increasing the delivery of energy substrates (e.g., fatty acids, glucose, ketones) to the mitochondria will be worthless if the mitochondria are unable to turn these energy substrates into fuel. Micronutrients (including coenzyme Q10, zinc, copper, selenium and iron) are required to efficiently convert macronutrients to ATP. However, up to 50% of patients with heart failure are deficient in one or more micronutrients in cross‐sectional studies. Micronutrient deficiency has a high impact on mitochondrial energy production and should be considered an additional factor in the heart failure equation, moving our view of the failing myocardium away from an “an engine out of fuel” to “a defective engine on a path to self‐destruction.” This summary of evidence suggests that supplementation with micronutrients—preferably as a package rather than singly—might be a potential therapeutic strategy in the treatment of heart failure patients.

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“…It was reported that double strand breaks of mtDNA are observed in iron-exposed mitochondria. Iron overload also leads to progressive loss of intact mtDNA, as well as reduced mtDNA transcription and decreased expression of respiratory chain subunits encoded by mitochondrial genome [103][104][105][106]. Conversely, preserving mitochondrial architecture and functionalities by utilizing distinct approaches was evidenced to protect cells from iron toxicity in multiple models.…”

Section: The Engagement Of Mitochondria In Iron Overload Associated Cell Damagementioning

confidence: 99%

The Multifaceted Regulation of Mitochondria in Ferroptosis

Wang

et al. 2021

Life

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Ferroptosis is characterized as a novel form of regulated cell death, which is initiated by the lethal accumulation of lipid peroxidation catalyzed by cellular labile free iron. This iron driven cell death sharply differs from other well characterized forms of regulated cell death at morphological, genetic and biochemical levels. Increasing research has elaborated a high relevance between dysregulated ferroptosis and the pathogenesis of degenerative diseases and organs injury in human patients. Additionally, targeted induction of ferroptosis is considered as a potentially therapeutic design for the clinical intervention of other therapy-resistant cancers. It is well understood that mitochondria, the cellular powerhouse, determine several types of regulated cell death. Recently, compromised mitochondrial morphology and functionalities have been primarily formulated in ferroptosis. Several mitochondria associated proteins and metabolic processes have been elaborated to fine-tune ferroptotic program. Herein, we critically review the recent advances in this booming field, with focus on summarizing the multifaceted mitochondrial regulation of ferroptosis and providing a perspective on the potential biochemical basis. Finally, we are attempting to shed light on an integrative view on the possibility of mitochondria- and ferroptosis-targeting therapeutics as novel treatment designs for the intervention of ferroptosis related diseases.

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Iron(II) induces changes in the conformation of mammalian mitochondrial DNA resulting in a reduction of its transcriptional rate

Cited by 11 publications

References 26 publications

DNA supercoiling suppresses real-time PCR: a new approach to the quantification of mitochondrial DNA damage and repair

DNA supercoiling suppresses real-time PCR: a new approach to the quantification of mitochondrial DNA damage and repair

Micronutrient deficiencies in heart failure: Mitochondrial dysfunction as a common pathophysiological mechanism?

The Multifaceted Regulation of Mitochondria in Ferroptosis

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