Respiratory supercomplexes: structure, function and assembly

Vartak, Rasika; Porras, Christina Ann-Marie; Bai, Yidong

doi:10.1007/s13238-013-3032-y

Cited by 79 publications

(60 citation statements)

References 79 publications

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“…As ubiquitous energy organelles, mitochondria provide most of the adenosine triphosphate (ATP) for cells through the respiratory chain comprising several complex and supercomplex (13). NADH-ubiquinone oxidoreductase is a complex containing 44 subunits.…”

Section: A Series Of Nbp Potential Targets Resulting From Search Are mentioning

confidence: 99%

“…Disassociation or mutation of this complex exists within many human disorders such as Leigh syndrome (14). Of note, pathological defects of mitochondrial respiration have a close correlation with both acute neuronal trauma and chronic neurodegenerative diseases (13). Metformin, as an inhibitor of NADHubiquinone oxidoreductase, is proved to exert protective role in ischemic stroke through suppression of ROS (reactive oxygen species).…”

Section: A Series Of Nbp Potential Targets Resulting From Search Are mentioning

confidence: 99%

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The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study

Wang

Zhang

et al. 2017

Quant. Imaging Med. Surg.

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Background: DL-3-n-butylphthalide (NBP) is a drug for treating acute ischemic stroke, and may play a neuroprotective role by acting on multiple active targets. The aim of this study was to predict the target proteins of NBP in mammalian cells. Methods:The similarity ensemble approach search tool (SEArch), one of the commonly used public bioinformatics tools for target prediction, was employed in the experiment. The molecular docking of NBP to target proteins was performed by using the three-dimensional (3-D) crystal structure, substrate free. The software AutoDock Vina was used for all dockings. The binding targets of NBP were illustrated as 3-D and 2-D diagrams.Results: Firstly, the results showed that NBP bounded to the same binding site on NAD(P)H quinone oxidoreductases (NQO1) as the substrate FAD, leading to competitive inhibition for the catalytic site with −7.2 kcal/mol. This might break the 3-D structure of NQO1 and bring about P53 degradation, resulting in a decrease of p53-mediated apoptosis in ischemic brain cells. Secondly, NBP might exert its therapeutic effect on acute ischemic stroke via modulating indoleamine 2,3-dioxygenase (IDO) bioactivity after associating with it. NBP could alleviate the depression following ischemic stroke by inhibiting IDO. Thirdly, NBP might modulate the function of NADH-ubiquinone oxidoreductase by competitively embedding itself into this complex, further affecting mitochondrial respiration in cerebrovascular diseases as an anti-oxidant agent.Conclusions: Three potential target proteins of NBP were identified, which may provide a novel aspect for better understanding the protective effects of NBP on the nervous system at the molecular level.

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Section: A Series Of Nbp Potential Targets Resulting From Search Are mentioning

confidence: 99%

Section: A Series Of Nbp Potential Targets Resulting From Search Are mentioning

confidence: 99%

The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study

Wang

Zhang

et al. 2017

Quant. Imaging Med. Surg.

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“…However, fewer papers reported that association of the mitochondrial respiratory chain complexes form higher supramolecular structures, which are called mitochondrial respiratory supercomplexes. These supercomplexes can take electrons from NADH to reduce oxygen (Acín-Pérez et al, 2008;Althoff et al, 2011;Vartak et al, 2013). Mitochondria exert a pivotal role in mediating cell proliferation and apoptosis (Zhang et al, 2007), and mitochondrial dysfunction is a hallmark of many genetic diseases and tumor progression.…”

Section: Discussionmentioning

confidence: 99%

PGC-1α regulates the cell cycle through ATP and ROS in CH1 cells

Yao

et al. 2016

J. Zhejiang Univ. Sci. B

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Abstract:Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) is a transcriptional co-activator involved in mitochondrial biogenesis, respiratory capacity, and oxidative phosphorylation (OXPHOS). PGC-1α plays an important role in cellular metabolism and is associated with tumorigenesis, suggesting an involvement in cell cycle progression. However, the underlying mechanisms mediating its involvement in these processes remain unclear. To elucidate the signaling pathways involved in PGC-1α function, we established a cell line, CH1 PGC-1α, which stably overexpresses PGC-1α. Using this cell line, we found that over-expression of PGC-1α stimulated extra adenosine triphosphate (ATP) and reduced reactive oxygen species (ROS) production. These effects were accompanied by up-regulation of the cell cycle checkpoint regulators CyclinD1 and CyclinB1. We hypothesized that ATP and ROS function as cellular signals to regulate cyclins and control cell cycle progression. Indeed, we found that reduction of ATP levels down-regulated CyclinD1 but not CyclinB1, whereas elevation of ROS levels down-regulated CyclinB1 but not CyclinD1. Furthermore, both low ATP levels and elevated ROS levels inhibited cell growth, but PGC-1α was maintained at a constant level. Together, these results demonstrate that PGC-1α regulates cell cycle progression through modulation of CyclinD1 and CyclinB1 by ATP and ROS. These findings suggest that PGC-1α potentially coordinates energy metabolism together with the cell cycle.

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“…Coenzyme Q and cytochrome c have also been shown to associate with RCS (15), and recent evidence indicates that there are two distinct pools of coenzyme Q that are dedicated to reducing equivalents from NADH or reduced flavin adenine dinucleotide (16). RCS assemble to facilitate more-efficient electron transfer and to allow the utilization of different electron transport pathways and substrates during oxidative phosphorylation, to stabilize complex I and other complexes, and to limit the production of reactive oxygen species (ROS) generated from electron transport during oxidative phosphorylation (8,14,(16)(17)(18)(19). Altogether, these effects support the importance of RCS for optimal mitochondrial function.…”

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confidence: 99%

Stomatin-Like Protein 2 Is Required for In Vivo Mitochondrial Respiratory Chain Supercomplex Formation and Optimal Cell Function

Mitsopoulos

Chang

Wai

et al. 2015

Molecular and Cellular Biology

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c Stomatin-like protein 2 (SLP-2) is a mainly mitochondrial protein that is widely expressed and is highly conserved across evolution. We have previously shown that SLP-2 binds the mitochondrial lipid cardiolipin and interacts with prohibitin-1 and -2 to form specialized membrane microdomains in the mitochondrial inner membrane, which are associated with optimal mitochondrial respiration. To determine how SLP-2 functions, we performed bioenergetic analysis of primary T cells from T cell-selective Slp-2 knockout mice under conditions that forced energy production to come almost exclusively from oxidative phosphorylation. These cells had a phenotype characterized by increased uncoupled mitochondrial respiration and decreased mitochondrial membrane potential. Since formation of mitochondrial respiratory chain supercomplexes (RCS) may correlate with more efficient electron transfer during oxidative phosphorylation, we hypothesized that the defect in mitochondrial respiration in SLP-2-deficient T cells was due to deficient RCS formation. We found that in the absence of SLP-2, T cells had decreased levels and activities of complex I-III 2 and I-III 2 -IV 1-3 RCS but no defects in assembly of individual respiratory complexes. Impaired RCS formation in SLP-2-deficient T cells correlated with significantly delayed T cell proliferation in response to activation under conditions of limiting glycolysis. Altogether, our findings identify SLP-2 as a key regulator of the formation of RCS in vivo and show that these supercomplexes are required for optimal cell function. S tomatin-like protein 2 (SLP-2) is a mainly mitochondrial protein that is widely expressed and is highly conserved across evolution (1-4). We have previously shown that SLP-2 binds the mitochondrial phospholipid cardiolipin and interacts with prohibitin-1 (PHB1) and PHB2, which are proposed to form specialized cardiolipin-enriched microdomains in the mitochondrial inner membrane important for optimal respiratory function (5, 6). Indeed, we showed that deletion of Slp-2 results in decreased cardiolipin microdomains and increased mitochondrial respiration uncoupled from ATP synthase activity, a defect overcome by an increased reliance on glycolysis (5).Recently, it has been shown that mitochondrial respiratory complexes are not randomly dispersed throughout the mitochondrial inner membrane but instead have supramolecular interactions allowing them to form respiratory chain supercomplexes (RCS) (7-10). RCS are commonly isolated from mitochondrial membranes with mild detergents, usually digitonin, followed by blue native (BN) polyacrylamide gel electrophoresis (PAGE), and their existence has been confirmed by electron microscopy and single-particle image processing (11,12). RCS occur mainly among complexes I, III, and IV (NADH-coenzyme Q reductase, ubiquinol-cytochrome c reductase, and cytochrome c oxidase, respectively) with various stoichiometries, whereas complex V (ATP synthase) can form dimers and oligomers (10, 13) and complex II (succinate-coenzyme Q reducta...

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Respiratory supercomplexes: structure, function and assembly

Cited by 79 publications

References 79 publications

The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study

The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study

PGC-1α regulates the cell cycle through ATP and ROS in CH1 cells

Stomatin-Like Protein 2 Is Required for In Vivo Mitochondrial Respiratory Chain Supercomplex Formation and Optimal Cell Function

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