Mitochondrial Dysfunction and Redox Imbalance as a Diagnostic Marker of “Free Radical Diseases”

doi:10.21873/anticanres.11963

Cited by 63 publications

(53 citation statements)

References 73 publications

(85 reference statements)

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“…Additionally, enrichment of mitochondria-localized proteins was also apparent in the second study examining proteomic differences between C1q-tagged synaptosomes of APP/PS1 mice compared to untagged ones. Functional disturbances of the mitochondria, caused by, e.g., damage to the mitochondrial DNA and agerelated functional decline can ultimately lead to increased mitochondrial ROS production that damages mitochondrial macromolecules and conveys elevated vulnerability for further adverse effects [52,53]. Thus, the detection of mitochondrial ROS can provide insight into the general functional state of the mitochondrion.…”

Section: Discussionmentioning

confidence: 99%

Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model

Győrffy

Tóth

Török

et al. 2020

Cell. Mol. Life Sci.

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Synaptic functional disturbances with concomitant synapse loss represent central pathological hallmarks of Alzheimer's disease. Excessive accumulation of cytotoxic amyloid oligomers is widely recognized as a key event that underlies neurodegeneration. Certain complement components are crucial instruments of widespread synapse loss because they can tag synapses with functional impairments leading to their engulfment by microglia. However, an exact understanding of the affected synaptic functions that predispose to complement-mediated synapse elimination is lacking. Therefore, we conducted systematic proteomic examinations on synaptosomes prepared from an amyloidogenic mouse model of Alzheimer's disease (APP/PS1). Synaptic fractions were separated according to the presence of the C1q-tag using fluorescence-activated synaptosome sorting and subjected to proteomic comparisons. The results raised the decline of mitochondrial functions in the C1q-tagged synapses of APP/PS1 mice based on enrichment analyses, which was verified using flow cytometry. Additionally, proteomics results revealed extensive alterations in the level of septin protein family members, which are known to dynamically form highly organized pre-and postsynaptic supramolecular structures, thereby affecting synaptic transmission. Highresolution microscopy investigations demonstrated that synapses with considerable amounts of septin-3 and septin-5 show increased accumulation of C1q in APP/PS1 mice compared to the wild-type ones. Moreover, a strong positive correlation was apparent between synaptic septin-3 levels and C1q deposition as revealed via flow cytometry and confocal microscopy examinations. In sum, our results imply that deterioration of synaptic mitochondrial functions and alterations in the organization of synaptic septins are associated with complement-dependent synapse loss in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model

Győrffy

Tóth

Török

et al. 2020

Cell. Mol. Life Sci.

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“…A potential means of using NPs for therapeutic purposes is related to their ability to modulate the level of oxidative stress, thus making them especially important in the context of the topic under consideration [ 28 ]. Free radicals such as reactive oxygen species (ROS), which are generated in the mitochondria during normal metabolic processes, are important second messengers that support signal transduction pathways implicated in normal cell functions including survival, proliferation, differentiation, and apoptosis [ 29 ]. Under normal physiological conditions, cellular ROS levels are strongly controlled by specific antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) and by exogenous antioxidants such as flavonoids, vitamin E, ascorbic acids, and glutathione (GSH) [ 30 ].…”

Section: Role Of Reactive Oxygen Species In Pathogenesis Of T2dmentioning

confidence: 99%

Metallic Nanoantioxidants as Potential Therapeutics for Type 2 Diabetes: A Hypothetical Background and Translational Perspectives

Lushchak

Zayachkivska

Vaiserman

2018

Oxidative Medicine and Cellular Longevity

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Hyperglycemia-induced overproduction of reactive oxygen species (ROS) is an important contributor to type 2 diabetes (T2D) pathogenesis. The conventional antioxidant therapy, however, proved to be ineffective for its treatment. This may likely be due to limited absorption profiles and low bioavailability of orally administered antioxidants. Therefore, novel antioxidant agents that may be delivered to specific target organs are actively developed now. Metallic nanoparticles (NPs), nanosized materials with a dimension of 1–100 nm, appear very promising for the treatment of T2D due to their tuned physicochemical properties and ability to modulate the level of oxidative stress. An excessive generation of ROS is considered to be the most common negative outcome related to the application of NPs. Several nanomaterials, however, were shown to exhibit enzyme-like antioxidant properties in animal models. Such NPs are commonly referred to as “nanoantioxidants.” Since NPs can provide specifically targeted or localized therapy, their use is a promising therapeutic option in addition to conventional therapy for T2D. NP-based therapies should certainly be used with caution given their potential toxicity and risk of adverse health outcomes. However, despite these challenges, NP-based therapeutic approaches have a great clinical potential and further translational studies are needed to confirm their safety and efficacy.

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“…In the mitochondrial free radical theory of aging accumulation of damaging mtDNA mutations, impairment of oxidative phosphorylation as well as an imbalance in the expression of antioxidant enzymes results in exponential overproduction of ROS. This elicited condition forms a "vicious cycle" that is the basis of a wide range of pathologies, termed as "free radical diseases" such as cancer, neurodegeneration, atherosclerosis, diabetes mellitus and chronic inflammation [8]. Importantly, besides the obvious induction of oxidative nucleotide damage to mtDNA, ROS promotes tumorigenesis through several other mechanisms, including stabilization of hypoxiainducible factor (HIF)-α, increased calcium flux, inactivation of key phosphatases, such as Pten and PP2A, and activation of both the NRF2 and NF-κB transcription factors [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

Errichiello¹,

Venesio²

2018

Mitochondrial DNA - New Insights

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Mitochondrial DNA alterations, including point mutations, deletions, inversions and copy number variations, have been widely reported in many age-related degenerative diseases and tumors. However, numerous studies investigating their pathogenic role in cancer have provided inconsistent evidence. Furthermore, biological impacts of mitochondrial DNA variants vary tremendously, depending on the proportion of mutant DNA molecules carried by the neoplastic cells (the so-called heteroplasmy). The recent discovery of inter-genomic crosstalk between nucleus and mitochondria has reinforced the role of mitochondrial DNA variants in perturbing this essential signaling pathway and thus indirectly targeting nuclear genes involved in tumorigenic and invasive phenotype. Therefore, mitochondrial dysfunction is currently considered a crucial hallmark of carcinogenesis as well as a promising target for anticancer therapy. This chapter describes the role of different types of mitochondrial DNA alterations by mainly considering the paradigmatic model of colorectal carcinogenesis and, in particular, it revisits the issue of whether mitochondrial mutations are causative cancer drivers or simply genuine passenger events. The advent of high-throughput next-generation sequencing techniques, as well as the development of genetic and pharmaceutical interventions for the treatment of mitochondrial dysfunction in cancer, are also discussed.

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Mitochondrial Dysfunction and Redox Imbalance as a Diagnostic Marker of “Free Radical Diseases”

Cited by 63 publications

References 73 publications

Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model

Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model

Metallic Nanoantioxidants as Potential Therapeutics for Type 2 Diabetes: A Hypothetical Background and Translational Perspectives

Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

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