Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat

Robb, Ellen L.; Gawel, Justyna M.; Aksentijević, Dunja; Cochemé, Helena M.; Stewart, Tessa; Shchepinova, Maria M.; He, Qing; Prime, Tracy A.; Bright, Thomas P.; James, Andrew M.; Shattock, Michael J.; Senn, Hans Martin; Hartley, Richard C.; Murphy, Michael P.

doi:10.1016/j.freeradbiomed.2015.08.021

Cited by 113 publications

(110 citation statements)

References 40 publications

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“…To test whether this effect could be due to ROS selectively generated within mitochondria, we used MitoParaquat (MitoPQ) which is specifically imported into the organelle and generates superoxide (

O_{2}^{∙ -}

) only in the mitochondrial matrix (Fig C; Robb et al , ). Superoxide can then be dismutated by MnSOD to H 2 O 2 , which can exit the mitochondria (Brand, ; Sies, ).…”

Section: Resultsmentioning

confidence: 99%

APOPT 1/ COA 8 assists COX assembly and is oppositely regulated by UPS and ROS

et al. 2018

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Loss‐of‐function mutations in APOPT1, a gene exclusively found in higher eukaryotes, cause a characteristic type of cavitating leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency. Although the genetic association of APOPT1 pathogenic variants with isolated COX defects is now clear, the biochemical link between APOPT1 function and COX has remained elusive. We investigated the molecular role of APOPT1 using different approaches. First, we generated an Apopt1 knockout mouse model which shows impaired motor skills, e.g., decreased motor coordination and endurance, associated with reduced COX activity and levels in multiple tissues. In addition, by achieving stable expression of wild‐type APOPT1 in control and patient‐derived cultured cells we ruled out a role of this protein in apoptosis and established instead that this protein is necessary for proper COX assembly and function. On the other hand, APOPT1 steady‐state levels were shown to be controlled by the ubiquitination–proteasome system (UPS). Conversely, in conditions of increased oxidative stress, APOPT1 is stabilized, increasing its mature intramitochondrial form and thereby protecting COX from oxidatively induced degradation.

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O_{2}^{∙ -}

) only in the mitochondrial matrix (Fig C; Robb et al , ). Superoxide can then be dismutated by MnSOD to H 2 O 2 , which can exit the mitochondria (Brand, ; Sies, ).…”

Section: Resultsmentioning

confidence: 99%

APOPT 1/ COA 8 assists COX assembly and is oppositely regulated by UPS and ROS

et al. 2018

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“…349 Mitochondria-targeted paraquat (MitoPQ, Chart 50) was shown to induce H 2 O 2 production in isolated mitochondria, and this redox cycling activity was dependent on the mitochondrial membrane potential. Also, MitoPQ induced MitoSOX oxidation, aconitase inactivation, and cell death of C2C12 myoblasts at concentrations ~1000-fold lower than observed for PQ.…”

Section: Mitochondria-targeted Probes and Sensors For Reactive Oxymentioning

confidence: 99%

“…Also, MitoPQ induced MitoSOX oxidation, aconitase inactivation, and cell death of C2C12 myoblasts at concentrations ~1000-fold lower than observed for PQ. 349 However, the identity(ies) of the species responsible for MitoSOX oxidation and the importance of the redox cycling activity of MitoPQ in the stimulation of MitoSOX oxidation and inhibition of aconitase activity in intact cells has yet to be determined.…”

Section: Mitochondria-targeted Probes and Sensors For Reactive Oxymentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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“…For example, many cancer cells have ineffective mitochondrial apoptosis that can be re-activated 96 . Another approach is to deplete antioxidant defences 97 , or to increase mitochondrial ROS production 98 , and combine these cell stressors with another cancer drug to induce synthetic lethality 97 .…”

Section: Harnessing Mitochondria To Kill Cellsmentioning

confidence: 99%

Mitochondria as a therapeutic target for common pathologies

Murphy

Hartley

2018

Nat Rev Drug Discov

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573

419

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Although the development of mitochondrial therapies has largely focused on diseases caused by mutations in mitochondrial DNA or in nuclear genes encoding mitochondrial proteins, it has emerged that mitochondrial dysfunction also contributes to the pathology of many common disorders, including neurodegeneration, metabolic disease, heart failure, ischaemia-reperfusion injury and protozoal infections. Mitochondria therefore represent an important drug target for these highly prevalent diseases. Several strategies aimed at therapeutically restoring mitochondrial function are emerging and a small number of agents have entered clinical trials. This review will discuss the opportunities and challenges faced for the further development of a mitochondrial pharmacology for common pathologies.

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Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat

Cited by 113 publications

References 40 publications

APOPT 1/ COA 8 assists COX assembly and is oppositely regulated by UPS and ROS

APOPT 1/ COA 8 assists COX assembly and is oppositely regulated by UPS and ROS

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Mitochondria as a therapeutic target for common pathologies

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