Powerhouse down: Complex II dissociation in the respiratory chain

Hwang, Ming-Shih; Rohlena, Jakub; Dong, Lan-Feng; Neužil, Jiřı́; Grimm, Stefan

doi:10.1016/j.mito.2014.06.001

Cited by 37 publications

(24 citation statements)

References 120 publications

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“…Bacterial and fungal laccase-containing proteins can oxidize polyphenols13. Mitochondrial-targeted polyphenols can, in turn, modulate mtROS levels3839. We were unable to observe polyphenol oxidase activity in vitro with human LACC1 protein purified under a variety of conditions and assessed against multiple different laccase substrates.…”

Section: Resultsmentioning

confidence: 83%

“…We considered mitochondrial enzymes critical in the generation of mtROS with which LACC1 might interact. SDHA is localized in the inner mitochondrial membrane and is a major subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain important for mtROS generation373839, such that we considered SDHA as a candidate through which LACC1 might cooperate with to modulate mtROS. Endogenous LACC1 and SDHA associated with each other in human MDMs (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes

et al. 2017

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Functional consequences for most inflammatory disease-associated loci are incompletely defined, including in the LACC1 (C13orf31) region. Here we show that human peripheral and intestinal myeloid-derived cells express laccase domain-containing 1 (LACC1); LACC1 is expressed in both the cytoplasm and mitochondria. Upon NOD2 stimulation of human macrophages, LACC1 associates with the NOD2-signalling complex, and is critical for optimal NOD2-induced signalling, mitochondrial ROS (mtROS) production, cytokine secretion and bacterial clearance. LACC1 constitutively associates with succinate dehydrogenase (SDH) subunit A, and amplifies pattern recognition receptor (PRR)-induced SDH activity, an important contributor to mtROS production. Relative to LACC1 Ile254, cells transfected with Crohn's disease-risk LACC1 Val254 or LACC1 with mutations of the nearby histidines (249,250) have reduced PRR-induced outcomes. Relative to LACC1 Ile254 carriers, Val254 disease-risk carrier macrophages demonstrate decreased PRR-induced mtROS, signalling, cytokine secretion and bacterial clearance. Therefore, LACC1 is critical for amplifying PRR-induced outcomes, an effect that is attenuated by the LACC1 disease-risk variant.

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Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes

et al. 2017

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“…During the course of apoptosis, SDHA and B, which encompass the SDH activity, are dislodged from the membrane-anchored complex. SDH activity continues to operate removing electrons from succinate to FAD and Fe-S clusters in released SDHA/B, but apart from SDHC/D, the membrane-bond ubiquinone oxireductase site, O 2 undergoes one-electron reduction producing O 2 •− , overflowing the cell with ROS culminating with apoptosis 50–52 . Thus, it is possible that under conditions in which CI and CII are unbalanced, like that seen in the XP-C cells, CII activity contributes to chronic H 2 O 2 generation and genomic instability, and consequently to driving the tumorigenic process.…”

Section: Discussionmentioning

confidence: 99%

Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress

Mori

Costa

Soltys

et al. 2017

Sci Rep

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Genomic instability drives tumorigenesis and DNA repair defects are associated with elevated cancer. Metabolic alterations are also observed during tumorigenesis, although a causal relationship between these has not been clearly established. Xeroderma pigmentosum (XP) is a DNA repair disease characterized by early cancer. Cells with reduced expression of the XPC protein display a metabolic shift from OXPHOS to glycolysis, which was linked to accumulation of nuclear DNA damage and oxidants generation via NOX-1. Using XP-C cells, we show that mitochondrial respiratory complex I (CI) is impaired in the absence of XPC, while complex II (CII) is upregulated in XP-C cells. The CI/CII metabolic shift was dependent on XPC, as XPC complementation reverted the phenotype. We demonstrate that mitochondria are the primary source of H2O2 and glutathione peroxidase activity is compromised. Moreover, mtDNA is irreversibly damaged and accumulates deletions. XP-C cells were more sensitive to the mitochondrial inhibitor antimycin A, an effect also prevented in XPC-corrected cells. Our results show that XPC deficiency leads to alterations in mitochondrial redox balance with a CI/CII shift as a possible adaptation to lower CI activity, but at the cost of sensitizing XP-C cells to mitochondrial oxidative stress.

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“…The SDHA/SDHB dimer separates from the matrix face of the mitochondrial inner membrane‐bound components of complex II (SDHC/D), that are required for the succinate‐quinone reductase activity and the coenzyme Q pool reduction (Figure A and B). This dissociation is Ca 2+ /ROS mediated and pH dependent . The released SDHA/B subunit‐complex, having no electron acceptor to react with, then generates uncontrolled and excessive ROS as superoxide at its FADH 2 domain promoting further mPTP formation and cell death induction .…”

Section: Relationship Of Redox Control Ca2+/ros Triggering To the MImentioning

confidence: 99%

“…This dissociation is Ca 2+ /ROS mediated and pH dependent. 134,135 The released SDHA/B subunit-complex, having no electron acceptor to react with, then generates uncontrolled and excessive ROS as superoxide at its FADH 2 domain promoting further mPTP formation and cell death induction. 134,136 This process represents a "ROS-induced ROS-release" event that will feed forward to accelerate greater pore opening and trigger cancer cell death.…”

Section: A Novel Triggering Role For Sdh/complex II In Mptp Activationmentioning

confidence: 99%

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

Ralph

Nozuhur

ALHulais

et al. 2019

Medicinal Research Reviews

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Over the last decade, three major advances have contributed in improving the response rates against cancer including, immunotherapy; greater understanding of the molecular, biochemical, and cellular mechanisms in carcinogenesis thereby providing drug targets; and identification of reliable biomarkers for early detection to facilitate the earlier stage treatment of disease. However, no single universal cancer cure has yet been found, although combinations from the above areas have steadily improved survival outcomes. Hence, chemotherapy remains a key component in the oncologist's arsenal for cancer therapy, despite frequent development of drug resistance and more aggressive cancers with onset of advanced stage metastases. The focus here is to explore the repurposing of old drugs that cause pro‐oxidative overload to overcome onset of resistance to chemotherapy and enhance chemotherapeutic responses, particularly against metastatic cancer. Excellent examples of US Food and Drug Administration approved drugs suitable for repurposing are the potent and specific thioreductase inhibitor auranofin and the nonsteroidal anti‐inflammatory drug, celecoxib. Recently, both drugs were shown to selectively target and kill metastatic cancer cells and cancer stem cells (CSCs), predominantly by promoting excessive mitochondrial reactive oxygen species. Thus, targeting intracellular redox systems of advanced stage metastatic cancer cells and CSCs can promote an overload of pro‐oxidative stress to activate the intrinsic pathway for programmed cell death. It is envisaged that more clinical studies will incorporate longer term use of repurposed drugs, such as auranofin or celecoxib, to target redox systems in cancer cells as part of common practice postcancer diagnosis, providing enhanced chemotherapeutic responses and increased cancer survival.

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Powerhouse down: Complex II dissociation in the respiratory chain

Cited by 37 publications

References 120 publications

Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes

Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes

Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

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