Mitochondrial Pharmacology: Its Future Is Now

Szeto, Hazel H.; James, Laura P.; Atkinson, Arthur J.

doi:10.1038/clpt.2014.177

Cited by 14 publications

(13 citation statements)

References 25 publications

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“…Several compounds targeting mitochondria are currently being tested in clinical trials for treatment of neurodegenerative diseases. Mitochondrial antioxidants appear to be especially interesting at preclinical level (Szeto et al, 2014 ). Coenzyme Q10 (CoQ10), a carrier of the electron transport chain of oxidative phosphorylation, has been shown to be neuroprotective by attenuating mitochondrial dysfunction and aging (Shetty et al, 2014 ).…”

Section: Treatment Strategies For Neurodegenerative Diseasesmentioning

confidence: 99%

Microglial cell dysregulation in brain aging and neurodegeneration

Bernhardi

Eugenı́n

2015

Front. Aging Neurosci.

461

342

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Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergoes phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of cytokines and an exacerbated inflammatory response to pathological changes. Whereas LPS increases nitric oxide (NO) secretion in microglia from young mice, induction of reactive oxygen species (ROS) predominates in older mice. Furthermore, there is accumulation of DNA oxidative damage in mitochondria of microglia during aging, and also an increased intracellular ROS production. Increased ROS activates the redox-sensitive nuclear factor kappa B, which promotes more neuroinflammation, and can be translated in functional deficits, such as cognitive impairment. Mitochondria-derived ROS and cathepsin B, are also necessary for the microglial cell production of interleukin-1β, a key inflammatory cytokine. Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists. Assessing this apparent contradiction, we have reported that TGFβ1 induction and activation of Smad3 signaling after inflammatory stimulation are reduced in adult mice. Other protective functions, such as phagocytosis, although observed in aged animals, become not inducible by inflammatory stimuli and TGFβ1. Here, we discuss data suggesting that mitochondrial and endolysosomal dysfunction could at least partially mediate age-associated microglial cell changes, and, together with the impairment of the TGFβ1-Smad3 pathway, could result in the reduction of protective activation and the facilitation of cytotoxic activation of microglia, resulting in the promotion of neurodegenerative diseases.

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Section: Treatment Strategies For Neurodegenerative Diseasesmentioning

confidence: 99%

Microglial cell dysregulation in brain aging and neurodegeneration

Bernhardi

Eugenı́n

2015

Front. Aging Neurosci.

461

342

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“…Due to the indispensable function in the processes of oxidative phosphorylation, Coenzyme Q-10 (CoQ-10) and its derivatives are the most prominent members in the family of Q/HQ [4][5][6][7]. Although the number of studies related to the chemical and redox features of CoQ family members has increased tremendously in the last three decades [8][9][10][11][12][13][14][15][16][17][18], many key features are still not well understood. In our last two publications we have shown that Coenzyme Q-1 (CoQ-1) and CoQ-10 undergo structural changes in strong alkaline environment or in the presence of Cytochrome P450 enzymes [19,20].…”

Section: Introductionmentioning

confidence: 99%

New insights into the chemistry of Coenzyme Q-0: A voltammetric and spectroscopic study

Gulaboski

Bogeski

Kokoškarova

et al. 2016

Bioelectrochemistry

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Coenzyme Q-0 (CoQ-0) is the only Coenzyme Q lacking an isoprenoid group on the quinoid ring, a feature important for its physico-chemical properties. Here, the redox behavior of CoQ-0 in buffered and non-buffered aqueous media was examined. In buffered aqueous media CoQ-0 redox chemistry can be described by a 2-electron-2-proton redox scheme, characteristic for all benzoquinones. In non-buffered media the number of electrons involved in the electrode reaction of CoQ-0 is still 2; however, the number of protons involved varies between 0 and 2. This results in two additional voltammetric signals, attributed to 2-electrons-1H + and 2-electrons-0H + redox processes, in which mono-and di-anionic compounds of CoQ-0 are formed. In addition, CoQ-0 exhibits a complex chemistry in strong alkaline environment. The reaction of CoQ-0 and OH − anions generates several hydroxyl derivatives as products. Their structures were identified with HPLC/MS. The prevailing radical reaction mechanism was analyzed by electron paramagnetic resonance spectroscopy. The hydroxyl derivatives of CoQ-0 have a strong antioxidative potential and form stable complexes with Ca 2+ ions. In summary, our results allow mechanistic insights into the redox properties of CoQ-0 and its hydroxylated derivatives and provide hints on possible applications.

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“…Endogenous and exogenous compounds impairing neuron apoptosis have been reported to act as inhibitors of CL peroxidation . Remarkably, owing to the fundamental function of CL–cyt c in cell apoptosis, new mitochondria‐targeted compounds, including electron acceptors, electron donors, and hydride acceptors, have been reported to regulate CL peroxidation and are potentially exploitable as anti‐ or pro‐apoptotic drugs . Over the last decade, several chemicals, including dopamine, L‐DOPA, minocycline, and nitroxide/gramicidin, have been reported to efficiently decrease the progression of degenerative diseases inhibiting apoptosis by impairing CL–cyt c peroxidase activity .…”

Section: Discussionmentioning

confidence: 99%

Cardiolipin-cytochromeccomplex: Switching cytochromecfrom an electron-transfer shuttle to a myoglobin- and a peroxidase-like heme-protein

et al. 2015

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Cytochrome c (cytc) is a small heme-protein located in the space between the inner and the outer membrane of the mitochondrion that transfers electrons from cytc-reductase to cytcoxidase. The hexa-coordinated heme-Fe atom of cytc displays a very low reactivity toward ligands and does not exhibit significant catalytic properties. However, upon cardiolipin (CL) binding, cytc achieves ligand binding and catalytic properties reminiscent of those of myoglobin and peroxidase. In particular, the peroxidase activity of the cardiolipin-cytochrome c complex (CL-cytc) is critical for the redistribution of CL from the inner to the outer mitochondrial membranes and is essential for the execution and completion of the apoptotic program. On the other hand, the capability of CL-cytc to bind NO and CO and the heme-Fe-based scavenging of reactive nitrogen and oxygen species may affect apoptosis. Here, the ligand binding and catalytic properties of CL-cytc are analyzed in parallel with those of CL-free cytc, myoglobin, and peroxidase to dissect the potential mechanisms of CL in modulating the proand anti-apoptotic actions of cytc. V C 2015 IUBMB Life, 67(2): [98][99][100][101][102][103][104][105][106][107][108][109] 2015

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Mitochondrial Pharmacology: Its Future Is Now

Cited by 14 publications

References 25 publications

Microglial cell dysregulation in brain aging and neurodegeneration

Microglial cell dysregulation in brain aging and neurodegeneration

New insights into the chemistry of Coenzyme Q-0: A voltammetric and spectroscopic study

Cardiolipin-cytochromeccomplex: Switching cytochromecfrom an electron-transfer shuttle to a myoglobin- and a peroxidase-like heme-protein

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