Selective Targeting of a Redox-active Ubiquinone to Mitochondria within Cells

By Geoffrey F. Kelso, C. M. Porteous, C. Coulter, G. Hughes, W. K. Porteous, E. Ledgerwood, Robin A. J. Smith, M. Murphy. Journal of Biological Chemistry, 2001

1,041 citations recorded by the source corpus.

With the recognition of the central role of mitochondria in apoptosis, there is a need to develop specific tools to manipulate mitochondrial function within cells. Here we report on the development of a novel antioxidant that selectively blocks mitochondrial oxidative damage, enabling the roles of mitochondrial oxidative stress in different types of cell death to be inferred. This antioxidant, named mitoQ, is a ubiquinone derivative targeted to mitochondria by covalent attachment to a lipophilic triphenylphosphonium cation through an aliphatic carbon chain. Due to the large mitochondrial membrane potential, the cation was accumulated within mitochondria inside cells, where the ubiquinone moiety inserted into the lipid bilayer and was reduced by the respiratory chain. The ubiquinol derivative thus formed was an effective antioxidant that prevented lipid peroxidation and protected mitochondria from oxidative damage. After detoxifying a reactive oxygen species, the ubiquinol moiety was regenerated by the respiratory chain enabling its antioxidant activity to be recycled. In cell culture studies, the mitochondrially localized antioxidant protected mammalian cells from hydrogen peroxide-induced apoptosis but not from apoptosis induced by staurosporine or tumor necrosis factor-α. This was compared with untargeted ubiquinone analogs, which were ineffective in preventing apoptosis. These results suggest that mitochondrial oxidative stress may be a critical step in apoptosis induced by hydrogen peroxide but not for apoptosis induced by staurosporine or tumor necrosis factor-α. We have shown that selectively manipulating mitochondrial antioxidant status with targeted and recyclable antioxidants is a feasible approach to investigate the role of mitochondrial oxidative damage in apoptotic cell death. This approach will have further applications in investigating mitochondrial dysfunction in a range of experimental models.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4a0ff745e3daa4f86c22e6446f1176c8c1c809c3

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Repurposing mitochondria from ATP production to ROS generation drives a pro-inflammatory phenotype in macrophages that depends on succinate oxidation by complex II (2016, background): “…Sigma-Aldrich Cat# H7904; CAS: 68047-06-3 Antimycin A Sigma-Aldrich Cat# A8674; CAS: 1397-94-0 MitoQ Laboratory of Rob Smith, Kelso et al., 2001 N/A MitoSOX Red mitochondrial superoxide indicator Molecular Probes Cat# M36008 CellROX Deep Red Molecular Probes Cat#…”
Mitochondrial dysfunction and oxidative stress in metabolic disorders - A Step towards mitochondria based therapeutic strategies (2016, background): “In the recent years, antioxidant compounds incorporating ubiquinone (MitoQ) or vitamin E (MitoVit E) specifically targeted to mitochondria have been successively used against mitochondrial dysfunctions [216] (Fig.”
Targeting an antioxidant to mitochondria decreases cardiac ischemia‐reperfusion injury (2005, methodology): “ubiquinol antioxidant by the respiratory chain (4).”
Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010, neutral): “Two such compounds (alkyltriphenylphosphonium cations) incorporating ubiquinone or vitamin E, termed mitoQ and mitoVit E, respectively, have been synthesized (162).”
Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. (2014, background): “Nowadays, after establishment of this mechanism (1), the approach started to serve two experimental missions: to deliver to the mitochondrial interior a desired compound which is bound to a mitochondriatropic vehicle (225, 393, 407) and, on the other hand, to discriminate between the mitochondrial a”