The DOI matches its Crossref record; 291 of the 292 references it cites were found in a registry or an index.
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
Abstract
Succinate:quinone reductase (SQR) of Complex II occupies a unique central point in the mitochondrial respiratory system as a major source of electrons driving reactive oxygen species (ROS) production. It is an ideal pharmaceutical target for modulating ROS levels in normal cells to prevent oxidative stress-induced damage or alternatively,increase ROS in cancer cells, inducing cell death.The value of drugs like diazoxide to prevent ROS production,protecting normal cells, whereas vitamin E analogues promote ROS in cancer cells to kill them is highlighted. As pharmaceuticals these agents may prevent degenerative disease and their modes of action are presently being fully explored. The evidence that SDH/Complex II is tightly coupled to the NADH/NAD+ ratio in all cells,impacted by the available supplies of Krebs cycle intermediates as essential NAD-linked substrates, and the NAD+-dependent regulation of SDH/Complex II are reviewed, as are links to the NAD+-dependent dehydrogenases, Complex I and the E3 dihiydrolipoamide dehydrogenase to produce ROS. This review collates and discusses diverse sources of information relating to ROS production in different biological systems, focussing on evidence for SQR as the main source of ROS production in mitochondria, particularly its relevance to protection from oxidative stress and to the mitochondrial-targeted anti cancer drugs (mitocans) as novel cancer therapies [corrected].
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“This seems to be especially the case for mutations in complex II subunits C and D located in the vicinity of the Qp site that have been associated with specific forms of cancer such as hereditary paragangliomas and pheochromocytomas (overview in [13,14,36]) and in SdhA that can cause Leigh syndrome, a progressive neurodegenerative disease [14,94].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [36]
In the citing paper
“This increased succinate pool under hypoxia might be supplied either from glutamate through α-ketoglutarate by transamination [76,77] or by a partial reversal of the TCA cycle from malate through fumarate, which requires that complex II would become a fumarate reductase under hypoxia [36,79].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [36]
In the citing paper
“It has been observed that loss of function of complex II can lead to the accumulation of succinate and increased ROS generation in mammalian cells (overview in [14,36]).”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [36]
In the citing paper
“While alternative explanations for the source or mechanism of ROS production under these conditions have been proposed [34,36], the prevalent view is that under these conditions ROS are produced by complex I due to RET from complex II [18][19][20]23].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [36]
In the citing paper
“This has not been considered in recent publications that have challenged the existence of a reverse electron transfer from complex II into complex I [36,110].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [36]
Citations
Cites
1 retracted
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Herb, M., & Schramm, M. (2021) · Antioxidants · doi:10.3390/antiox10020313 · Cited by 633
Molecular Mechanisms of Superoxide Production by the Mitochondrial Respiratory Chain
Dröse, S., & Brandt, U. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3573-0_6 · Cited by 537
Kausar, S., Wang, F., & Cui, H. (2018) · Cells · doi:10.3390/cells7120274 · Cited by 327
Cadmium-Induced Kidney Injury: Oxidative Damage as a Unifying Mechanism
Yan, L., & Allen, D. C. (2021) · Biomolecules · doi:10.3390/biom11111575 · Cited by 297
Classification of mitocans, anti-cancer drugs acting on mitochondria
Neužil, J., Dong, L., Rohlena, J., Truksa, J., & Ralph, S. J. (2012) · Mitochondrion · doi:10.1016/j.mito.2012.07.112 · Cited by 255
Self-citation
Metadata
- Authors
- Ralph, S. J., Moreno-Sánchez, R., Neuzil, J., & Rodríguez-Enríquez, S.
- Affiliations
- Griffith University (AU)
- Corresponding author
- Ralph, Stephen J.
- ORCID
- Ralph, Stephen J.
- Venue
- Pharmaceutical Research
- Published
- 2011-08-24
- Volume
- 28
- Issue
- 11
- Pages
- 2695-2730
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- OpenAlex
- W1983521123
- Cited by
- 126
- References
- 292
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 12 · 2023: 12 · 2022: 6 · 2021: 12 · 2020: 11 · 2019: 8 · 2018: 9 · 2017: 9 · 2016: 5 · 2015: 9 · 2014: 12 · 2013: 6 · 2012: 9
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Pharmaceutical Research (publishedVersion)
- PubMed (publishedVersion)
- ASEP (submittedVersion, public-domain)
- Griffith Research Online (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- succinate dehydrogenase, mitochondrial reactive oxygen species, oxidative stress, ischemic injury, cancer cell death, diazoxide, vitamin E analogues, NAD+/NADH ratio, Krebs cycle intermediates, NAD-dependent dehydrogenase, mitocans
- MeSH terms
- Coenzyme A, Fatty Acids, Nonesterified, Humans, Dihydrolipoamide Dehydrogenase, Mitochondria, Neoplasms, Organophosphorus Compounds, Ubiquinone, NAD(P)H Dehydrogenase (Quinone), Cell Death, Reactive Oxygen Species, Succinic Acid, Protective Agents, alpha-Tocopherol
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