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Inhibitors of Succinate: Quinone Reductase/Complex II Regulate Production of Mitochondrial Reactive Oxygen Species and Protect Normal Cells from Ischemic Damage but Induce Specific Cancer Cell Death

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An Erratum to this article was published on 13 September 2011

ABSTRACT

Succinate:quinone reductase (SQR) of Complex II, occupying a unique central point in the mitochondrial respiratory system as a major source of electrons driving reactive oxygen species (ROS) production, is an ideal pharmaceutical target for modulating ROS levels in normal cells to prevent oxidative stress-induced damage or increase ROS in cancer cells, inducing cell death. Value of drugs like diazoxide to prevent ROS production, protecting normal cells, while vit. E analogues promote ROS in cancer cells to kill them, is highlighted. As pharmaceuticals, agents may prevent degenerative disease; their modes of action are being fully explored. Evidence that SDH/Complex II is tightly coupled to NADH/NAD+ ratio in all cells, impacted by available supplies of Krebs cycle intermediates as essential NAD-linked substrates, and NAD+-dependent regulation of SDH/Complex II are reviewed, as are links to NAD+-dependent dehydrogenases, Complex I and E3 dihiydrolipoamide dehydrogenase to produce ROS. We collate and discuss diverse sources of information relating to ROS production in different biological systems, focussing on evidence for SQR as main source of ROS production in mitochondria, particularly its relevance to protection from oxidative stress and to mitochondrial-targeted anticancer drugs (mitocans) as novel cancer therapies.

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Abbreviations

α-TOS:

alpha-tocopheryl succinate

∆μH + :

electrochemical H+ gradient across the inner mitocondrial membrane

2-OG:

2-oxoglutarate

2-OGDH:

2-oxoglutarate dehydrogenase

3-BrPyr:

3-bromopyruvate

ANT:

adenine nucleotide translocator

DCA:

dichloroacetate

DCPIP:

dichlorophenolindophenol

DLD:

dihydrolipoamide dehydrogenase

FFAs:

free fatty acids

FH:

fumarate hydratase

MCA:

metabolic control analysis

MPTP:

mitochondrial permeability transition pore

O2 −•:

superoxide

OAA:

oxaloacetate

OXPHOS:

oxidative phosphorylation

PDH:

pyruvate dehydrogenase

SDH:

succinate dehydrogenase

SMPs:

submitochondrial particles

SOD:

superoxide dismutase

SQR:

succinate quinone reductase

TTFA:

thenoyltrifluoroacetone

UQ:

ubiquinone

UQH:

semiquinone

UQH2 :

ubiquinol

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Authors and Affiliations

  1. School of Medical Science & Health Research Institute, Griffith University, Gold Coast, QLD, Australia, 4222

    Stephen J. Ralph & Jiri Neuzil

  2. Departamento de Bioquímica, Instituto Nacional de Cardiología, Tlalpan, México, DF 14080, Mexico

    Rafael Moreno-Sánchez & Sara Rodríguez-Enríquez

  3. Molecular Therapy Group, Institute of Biotechnology, Academy of Science of the Czech Republic, Prague 4, 142 20, Czech Republic

    Jiri Neuzil

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  1. Stephen J. Ralph
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Correspondence to Stephen J. Ralph.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s11095-011-0583-6

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Ralph, S.J., Moreno-Sánchez, R., Neuzil, J. et al. Inhibitors of Succinate: Quinone Reductase/Complex II Regulate Production of Mitochondrial Reactive Oxygen Species and Protect Normal Cells from Ischemic Damage but Induce Specific Cancer Cell Death. Pharm Res 28, 2695–2730 (2011). https://doi.org/10.1007/s11095-011-0566-7

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