Evidence for Detrimental Cross Interactions between Reactive Oxygen and Nitrogen Species in Leber’s Hereditary Optic Neuropathy Cells

Falabella, Micol; Forte, Elena; Magnifico, Maria Chiara; Santini, P.; Arese, Marzia; Giuffrè, Alessandro; Radić, Kristina; Chessa, Luciana; Coarelli, Giulia; Buscarinu, Maria Chiara; Mechelli, Rosella; Salvetti, Marco; Sarti, Paolo

doi:10.1155/2016/3187560

Cited by 8 publications

(4 citation statements)

References 51 publications

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“…There is some evidence suggesting that the exposure to high nitric oxide concentrations could impair in vivo the ability to cope with the oxidative stress caused by the genetic defect, thereby driving the pathology in LHON. This was described by Flabella et al in one patient carrying the 11788/ND4 mutation [96]. This same increase in ROS was described in MS as previously discussed [3,50,51].…”

Section: Mitochondrial Mutations In Multiple Sclerosis and Overlapsupporting

confidence: 77%

Mitochondrial Dysfunction and Multiple Sclerosis

Barcelos

Troxell

Graves

2019

Biology

165

132

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In recent years, several studies have examined the potential associations between mitochondrial dysfunction and neurodegenerative diseases such as multiple sclerosis (MS), Parkinson’s disease and Alzheimer’s disease. In MS, neurological disability results from inflammation, demyelination, and ultimately, axonal damage within the central nervous system. The sustained inflammatory phase of the disease leads to ion channel changes and chronic oxidative stress. Several independent investigations have demonstrated mitochondrial respiratory chain deficiency in MS, as well as abnormalities in mitochondrial transport. These processes create an energy imbalance and contribute to a parallel process of progressive neurodegeneration and irreversible disability. The potential roles of mitochondria in neurodegeneration are reviewed. An overview of mitochondrial diseases that may overlap with MS are also discussed, as well as possible therapeutic targets for the treatment of MS and other neurodegenerative conditions.

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Section: Mitochondrial Mutations In Multiple Sclerosis and Overlapsupporting

confidence: 77%

Mitochondrial Dysfunction and Multiple Sclerosis

Barcelos

Troxell

Graves

2019

Biology

165

132

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“…Bioavailability of NO at cell level depends on the activity of the NOS isoforms, so that physiological pathways ascribable to eNOS activity are featured by a limited (nM) amount of NO, whereas higher NO concentrations ( μ M) resulting from the activation of iNOS are responsible for structural modifications such as membrane lipid peroxydation and protein nitrosation. These modifications are associated to the onset and maintenance of severe inflammatory states, including atherosclerosis [ 34 , 55 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

VLDL Induced Modulation of Nitric Oxide Signalling and Cell Redox Homeostasis in HUVEC

Magnifico

Oberkersch

Mollo

et al. 2017

Oxidative Medicine and Cellular Longevity

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High levels of circulating lipoprotein constitute a risk factor for cardiovascular diseases, and in this context, the specific role of the very-low-density lipoproteins (VLDL) is poorly understood. The response of human umbilical vein endothelial cells (HUVEC) to VLDL exposure was studied, especially focusing on the pathways involved in alteration of redox homeostasis and nitric oxide (NO) bioavailability. The results obtained by the analysis of the expression level of genes implicated in the NO metabolism and oxidative stress response indicated a strong activation of inducible NO synthase (iNOS) upon 24 h exposure to VLDL, particularly if these have been preventively oxidised. Simultaneously, both mRNA and protein expression of endothelial NO synthase (eNOS) were decreased and its phosphorylation pattern, at the key residues Tyr495 and Ser1177, strongly suggested the occurrence of the eNOS uncoupling. The results are consistent with the observed increased production of nitrites and nitrates (NOx), reactive oxygen species (ROS), 3-nitrotyrosine (3-NT), and, at mitochondrial level, a deficit in mitochondrial O2 consumption. Altogether, these data suggest that the VLDL, particularly if oxidised, when allowed to persist in contact with endothelial cells, strongly alter NO bioavailability, affecting redox homeostasis and mitochondrial function.

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“…Peripheral blood mononuclear cells (PBMC) are used to establish lymphoblast cell lines that have mainly been used for biochemical analyses, viability assays, or to compare the degree of OXPHOS (oxidative phosphorylation) impairment in LHON. PBMCs, similarly to RGCs, have a metabolism mainly sustained by OXPHOS and therefore represent a good model to be investigated in LHON research (Falabella et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Testosterone increases apoptotic cell death and decreases mitophagy in Leber’s hereditary optic neuropathy cells

et al. 2020

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Leber's hereditary optic neuropathy (LHON) is one of the most common mitochondrial diseases caused by point mutations in mitochondrial DNA (mtDNA). The majority of diagnosed LHON cases are caused by a point mutation at position 11,778 in the mitochondrial genome. LHON mainly affects young men in their 20s and 30s with usually poor visual prognosis. It remains unexplained why men are more likely to develop the disease and why only retinal ganglion cells are affected. In this study, a cell model was used for the first time to investigate the influence of testosterone on the cell death mechanism apoptosis and on an autophagy/mitophagy. Cells with m.11778G > A were found to be significantly more susceptible to nucleosome formation and effector caspase activation that serve as hallmarks of apoptotic cell death. Cells having this mutation expressed higher levels of mitophagic receptors BNIP3 and BNIP3L/Nix in a medium with testosterone. Moreover, cells having the mutation exhibited greater mitochondrial mass, which suggests these cells have a decreased cell survival. The observed decrease in cell survival was supported by the observed increase in apoptotic cell death. Autophagy was analyzed after inhibition with Bafilomycin A1 (Baf A1). The results indicate impairment in autophagy in LHON cells due to lower autophagic flux supported by observed lower levels of autophagosome marker LC3-II. The observed impaired lower autophagic flux in mutant cells correlated with increased levels of BNIP3 and BNIP3L/Nix in mutant cells.

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Evidence for Detrimental Cross Interactions between Reactive Oxygen and Nitrogen Species in Leber’s Hereditary Optic Neuropathy Cells

Cited by 8 publications

References 51 publications

Mitochondrial Dysfunction and Multiple Sclerosis

Mitochondrial Dysfunction and Multiple Sclerosis

VLDL Induced Modulation of Nitric Oxide Signalling and Cell Redox Homeostasis in HUVEC

Testosterone increases apoptotic cell death and decreases mitophagy in Leber’s hereditary optic neuropathy cells

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