The nuclear encoded subunits of complex I from bovine heart mitochondria

Hirst, Judy; Carroll, Joe; Fearnley, Ian M.; Shannon, Richard J.; Walker, John E.

doi:10.1016/s0005-2728(03)00059-8

Cited by 354 publications

(415 citation statements)

References 119 publications

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“…Complex I is the largest complex in the MRC containing at least 46 subunits. 20,21 It has been shown previously that IFN-b/RA treatment increases the mRNA level of GRIM-19 in human breast carcinoma cell lines. 10 In this study, we investigated whether IFN-b/RA treatment can also stimulate expression of other MRC subunits in these cancer cell lines.…”

Section: Resultsmentioning

confidence: 95%

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

Huang

Chen

et al. 2006

Cell Death Differ

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Combination of retinoic acids (RAs) and interferons (IFNs) has synergistic apoptotic effects and is used in cancer treatment. However, the underlying mechanisms remain unknown. Here, we demonstrate that mitochondrial respiratory chain (MRC) plays an essential role in the IFN-b/RA-induced cancer cell death. We found that IFN-b/RA upregulates the expression of MRC complex subunits. Mitochondrial-nuclear translocation of these subunits was not observed, but overproduction of reactive oxygen species (ROS), which causes loss of mitochondrial function, was detected upon IFN-b/RA treatment. Knockdown of GRIM-19 (gene associated with retinoid-interferon-induced mortality-19) and NDUFS3 (NADH dehydrogenase (ubiquinone) Fe-S protein 3), two subunits of MRC complex I, by siRNA in two cancer cell lines conferred resistance to IFN-b/RA-induced apoptosis and reduced ROS production. In parallel, expression of late genes induced by IFN-b/RA that are directly involved in growth inhibition and cell death was also repressed in the knockdown cells. Our data suggest that the MRC regulates IFN-b/RA-induced cell death by modulating ROS production and late gene expression.

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Section: Resultsmentioning

confidence: 95%

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

Huang

Chen

et al. 2006

Cell Death Differ

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“…The caspase inhibitors z-VAD-fmk and DEVD-fmk have a partial effect, whereas the GB inhibitor Ac-IETD-CHO prevented NDUFV1 cleavage. Using CutDB and SitePrediction bioinformatics tool, 26,27 we found that GB has predicted cleavage sites for NDUFV1, NDUFS2, NDUFS1, NDUFS3, NDUFS7 and NDUFA13. Similar to NDUFV1, both NDUFS1 and NDUFS2 were cleaved in K562 cells treated with GB and P similarly to PARP-1 ( Figure 1f and data not shown).…”

Section: Resultsmentioning

confidence: 99%

Granzyme B-induced mitochondrial ROS are required for apoptosis

et al. 2014

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Caspases and the cytotoxic lymphocyte protease granzyme B (GB) induce reactive oxygen species (ROS) formation, loss of transmembrane potential and mitochondrial outer membrane permeabilization (MOMP). Whether ROS are required for GBmediated apoptosis and how GB induces ROS is unclear. Here, we found that GB induces cell death in an ROS-dependent manner, independently of caspases and MOMP. GB triggers ROS increase in target cell by directly attacking the mitochondria to cleave NDUFV1, NDUFS1 and NDUFS2 subunits of the NADH: ubiquinone oxidoreductase complex I inside mitochondria. This leads to mitocentric ROS production, loss of complex I and III activity, disorganization of the respiratory chain, impaired mitochondrial respiration and loss of the mitochondrial cristae junctions. Furthermore, we have also found that GB-induced mitocentric ROS are necessary for optimal apoptogenic factor release, rapid DNA fragmentation and lysosomal rupture. Interestingly, scavenging the ROS delays and reduces many of the features of GB-induced death. Consequently, GB-induced ROS significantly promote apoptosis. Cell Death and Differentiation (2015) 22, 862-874; doi:10.1038/cdd.2014.180; published online 31 October 2014To induce cell death, human granzyme B (GB) activates effector caspase-3 or acts directly on key caspase substrates, such as the proapoptotic BH3 only Bcl-2 family member Bid, inhibitor of caspase-activated DNase (ICAD), poly-(ADPribose) polymerase-1 (PARP-1), lamin B, nuclear mitotic apparatus protein 1 (NUMA1), catalytic subunit of the DNAdependent protein kinase (DNA-PKcs) and tubulin. [1][2][3] Consequently, caspase inhibitors have little effect on human GB-mediated cell death and DNA fragmentation. 2 GB causes reactive oxygen species (ROS) production, dissipation of the mitochondrial transmembrane potential (ΔΨm) and MOMP, which leads to the release of apoptogenic factors such as cytochrome c (Cyt c), HtrA2/Omi, endonuclease G (Endo G), Smac/Diablo and apoptosis-inducing factor, from the mitochondrial intermembrane space to the cytosol. [4][5][6][7][8][9][10][11] Interestingly, cells deficient for Bid, Bax and Bak are still sensitive to human GB-induced cell death, 5,11-13 suggesting that human GB targets the mitochondria in another way that needs to be characterized. Altogether, much attention has been focused on the importance of MOMP in the execution of GB-mediated cell death, leaving unclear whether ROS production is a bystander effect or essential to the execution of GBinduced apoptosis. The mitochondrial NADH: ubiquinone oxidoreductase complex I is a key determinant in steadystate ROS production. This 1 MDa complex, composed of 44 subunits, 14 couples the transfer of two electrons from NADH to ubiquinone with the translocation of four protons to generate the ΔΨm. The importance of ROS has been previously demonstrated for caspase-3 and granzyme A (GA) pathways through the cleavage of NDUFS1 and NDUFS3, respectively. [15][16][17][18] GA induces cell death in a Bcl-2-insensitive and caspase-and MOMP-indepen...

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“…al. has suggested that the 75 kDa subunit is associated structurally with the 51-and 24 kDa subunits of the Fp subcomplex based on the structural homology related to the α (51 and 24 kDa) and γ (75 kDa) subunits of the NAD-reducing hydrogenases and that the NuoE, F and G subunits of E. coli Complex I can be co-expressed to form a catalytically active recombinant subcomplex (1,34,35). The information of X-ray structure from T. thermophilius Complex I supports this prediction (32).…”

Section: Protein S -Glutathiolation In the 75 Kda Subunit Of Nqrmentioning

confidence: 99%

Site-Specific S-Glutathiolation of Mitochondrial NADH Ubiquinone Reductase

et al. 2007

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The generation of reactive oxygen species in mitochondria acts as a redox signal in triggering cellular events such as apoptosis, proliferation, and senescence. Overproduction of superoxide (O 2 ·-) and O 2 ·--derived oxidants change the redox status of the mitochondrial GSH pool. An electron transport protein, Mitochondrial Complex I, is the major host of reactive/regulatory protein thiols. An important response of protein thiols to oxidative stress is to reversibly form protein mixed disulfide via S-glutathiolation. Exposure of Complex I to oxidized GSH, GSSG, resulted in specific Sglutathiolation at the 51 kDa and 75 kDa subunits. Here, to investigate the molecular mechanism of S-glutathiolation of Complex I, we prepared isolated bovine Complex I under non-reducing conditions and employed the techniques of mass spectrometry and EPR spin trapping for analysis. LC/MS/MS analysis of tryptic digests of the 51 kDa and 75 kDa polypeptides from glutathiolated Complex I (GS-NQR) revealed that two specific cysteines (C 206 and C 187 ) of the 51 kDa subunit and one specific cysteine (C 367 ) of the 75 kDa subunit were involved in redox modifications with GS binding. The electron transfer activity (ETA) of GS-NQR in catalyzing NADH oxidation by Q 1 was significantly enhanced. However, O 2 ·-generation activity (SGA) mediated by GS-NQR suffered a mild loss as measured by EPR spin trapping, suggesting the protective role of Sglutathiolation in the intact Complex I. Exposure of NADH dehydrogenase (NDH), the flavin subcomplex of Complex I, to GSSG resulted in specific S-glutathiolation on the 51 kDa subunit. Both ETA and SGA of S-glutathiolated NDH (GS-NDH) decreased in parallel as the dosage of GSSG increased. LC/MS/MS analysis of a tryptic digest of the 51 kDa subunit from GS-NDH revealed that C 206 , C 187 , and C 425 were glutathiolated. C 425 of the 51 kDa subunit is a ligand residue of the 4Fe-4S N3 center, suggesting that destruction of 4Fe-4S is the major mechanism involved in the inhibiton of NDH. The result also implies that S-glutathiolation of the 75 kDa subunit may play a role in protecting the 4Fe-4S cluster of the 51 kDa subunit from redox modification when Complex I is exposed to redox change in the GSH pool.Mitochondrial Complex I (EC 1.6.5.3. NADH:ubiquinone oxidoreductase) is the first energyconserving segment of the electron transport chain (ETC) (1-3). The enzyme catalyzes electron transfer from NADH to ubiquinone coupled with the translocation of four protons across the

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The nuclear encoded subunits of complex I from bovine heart mitochondria

Cited by 354 publications

References 119 publications

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

Granzyme B-induced mitochondrial ROS are required for apoptosis

Site-Specific S-Glutathiolation of Mitochondrial NADH Ubiquinone Reductase

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