Mitochondrial targeting of quinones: Therapeutic implications

Cochemé, Helena M.; Kelso, Geoffrey F.; James, Andrew M.; Ross, Meredith F.; Trnka, Ján; Mahendiran, Thabo; Asin-Cayuela, Jorge; Blaikie, Frances H.; Manas, Abdul-Rahman B.; Porteous, Carolyn M.; Adlam, Victoria J.; Smith, Robin A.J.; Murphy, Michael P.

doi:10.1016/j.mito.2007.02.007

Cited by 118 publications

(77 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While results with α-tocopherol are promising, recent reports have suggested that γ-tocopherol may be a more effective therapeutic agent in treating diseases involving oxidant stress and inflammation due to its potent anti-inflammatory activity [159,160]. Furthermore, Murphy and colleagues have developed novel strategies to "target" traditional antioxidants, like vitamin E, ubiquinone, and lipoic acid to the mitochondrion by attaching them to a lipophilic triphenylphosphonium moiety [161][162][163]. This modification allows the antioxidant to accumulate several-hundred fold in the mitochondrion in response to the mitochondrial membrane potential where it can exert maximum benefit.…”

Section: Are Antioxidants Feasible Treatments For Fatty Liver Disease?mentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

388

302

View full text Add to dashboard Cite

Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

show abstract

Section: Are Antioxidants Feasible Treatments For Fatty Liver Disease?mentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

388

302

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…MitoQ is orally active and is being pursued as a potential therapy in degenerative conditions, such as Parkinson disease (2). Although initially designed as an antioxidant, mitochondrial redox cycling of mitoquinone has been shown to lead to superoxide production and apoptotic cell death (6,7).…”

mentioning

confidence: 99%

The Antioxidant Transcription Factor Nrf2 Negatively Regulates Autophagy and Growth Arrest Induced by the Anticancer Redox Agent Mitoquinone

Rao

Klein

Bonar

et al. 2010

Journal of Biological Chemistry

123

134

View full text Add to dashboard Cite

Mitoquinone (MitoQ) is a synthetically modified, redox-active ubiquinone compound that accumulates predominantly in mitochondria. We found that MitoQ is 30-fold more cytotoxic to breast cancer cells than to healthy mammary cells. MitoQ treatment led to irreversible inhibition of clonogenic growth of breast cancer cells through a combination of autophagy and apoptotic cell death mechanisms. Relatively limited cytotoxicity was seen with the parent ubiquinone coenzyme Q 10. Inhibition of cancer cell growth by MitoQ was associated with G 1 /S cell cycle arrest and phosphorylation of the checkpoint kinases Chk1 and Chk2. The possible role of oxidative stress in MitoQ activity was investigated by measuring the products of hydroethidine oxidation. Increases in ethidium and dihydroethidium levels, markers of one-electron oxidation of hydroethidine, were observed at cytotoxic concentrations of MitoQ. Keap1, an oxidative stress sensor protein that regulates the antioxidant transcription factor Nrf2, underwent oxidation, degradation, and dissociation from Nrf2 in MitoQ-treated cells. Nrf2 protein levels, nuclear localization, and transcriptional activity also increased following MitoQ treatment. Knockdown of Nrf2 caused a 2-fold increase in autophagy and an increase in G 1 cell cycle arrest in response to MitoQ but had no apparent effect on apoptosis. The Nrf2-regulated enzyme NQO1 is partly responsible for controlling the level of autophagy. Keap1 and Nrf2 act as redox sensors for oxidative perturbations that lead to autophagy. MitoQ and similar compounds should be further evaluated for novel anticancer activity.Mitochondria are central to many cellular processes, including energy production and apoptosis. A by-product of electron transfer in the mitochondria is the formation of superoxide.

show abstract

Mitochondrial targeting of quinones: Therapeutic implications

Cited by 118 publications

References 66 publications

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

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

The Antioxidant Transcription Factor Nrf2 Negatively Regulates Autophagy and Growth Arrest Induced by the Anticancer Redox Agent Mitoquinone

Contact Info

Product

Resources

About