Investigation of the mechanism of proton translocation by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria: does the enzyme operate by a Q-cycle mechanism?

Sherwood, Sylvia; Hirst, Judy

doi:10.1042/bj20060766

Cited by 42 publications

(27 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NDUFV1 is a 51 kDa iron-sulfur (Fe-S) cluster-containing subunit that catalyzes the initial transfer of electrons from NADH across complex I to ubiquinone, making it a good candidate target for GB-induced ROS. [22][23][24][25] GB and P treatment of K562 cells induced a dose-and time-dependent cleavage of NDUFV1 comparable to PARP-1 cleavage (Figure 1e). The caspase inhibitors z-VAD-fmk and DEVD-fmk have a partial effect, whereas the GB inhibitor Ac-IETD-CHO prevented NDUFV1 cleavage.…”

Section: Resultsmentioning

confidence: 82%

Granzyme B-induced mitochondrial ROS are required for apoptosis

et al. 2014

View full text Add to dashboard Cite

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...

show abstract

Section: Resultsmentioning

confidence: 82%

Granzyme B-induced mitochondrial ROS are required for apoptosis

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The limited knowledge about the mechanism of electron transfer of Complex I makes it difficult to predict the mechanism by which this respiratory chain complex uses redox energy to translocate protons across the inner mitochondrial membrane (for reviews see [52][53][54]). …”

Section: Structure and Function Of Complex I: General Aspectsmentioning

confidence: 99%

Generation of Reactive Oxygen Species by Mitochondrial Complex I: Implications in Neurodegeneration

et al. 2008

View full text Add to dashboard Cite

Mitochondrial Complex I [NADH Coenzyme Q (CoQ) oxidoreductase] is the least understood of respiratory complexes. In this review we emphasize some novel findings on this enzyme that are of relevance to the pathogenesis of neurodegenerative diseases. Besides CoQ, also oxygen may be an electron acceptor from the enzyme, with generation of superoxide radical in the mitochondrial matrix. The site of superoxide generation is debated: we present evidence based on the rational use of several inhibitors that the one-electron donor to oxygen is an iron-sulphur cluster, presumably N2. On this assumption we present a novel mechanism of electron transfer to the acceptor, CoQ. Complex I is deeply involved in pathological changes, including neurodegeneration. Complex I changes are involved in common neurological diseases of the adult and old ages. Mitochondrial cytopathies due to mutations of either nuclear or mitochondrial DNA may represent a useful model of neurodegeneration. In this review we discuss Parkinson's disease, where the pathogenic involvement of Complex I is better understood; the accumulated evidence on the mode of action of Complex I inhibitors and their effect on oxygen radical generation is discussed in terms of the aetiology and pathogenesis of the disease.

show abstract

“…Then we fitted the value of the probability rate constant for O .-2 formation using data from (Kussmaul and Hirst, 2006). Fig.4a shows the simulated reduction of 100 μM Q by 100 μM NADH catalysed by 15 mg.ml -1 Complex I without O 2 compared to experimental data in (Sherwood and Hirst, 2006). Fig.4b and fig.4c show the simulated dependence of O .-2 production on [NADH] compared to experimental data in (Kussmaul and Hirst, 2006).…”

Section: Comparison To Experimental Datamentioning

confidence: 99%

“…Fig.4d shows the simulated linear dependence of O .-2 production on O 2 concentration (% saturated in air) at 30 μM NADH compared to experimental data in (Kussmaul and Hirst, 2006). tivity and ROS production compared to experimental data taken from (Sherwood and Hirst, 2006) and (Kussmaul and Hirst, 2006). In (b) to (d) Vros stands for the rate of formation of O .-2 in nmol/min/mg of Complex I.…”

Section: Comparison To Experimental Datamentioning

confidence: 99%

“…We first considered other possible fixed parameters values and used a tabu search algorithm for the binding and dissociation constants, to fit the results of our numerical simulations with experimental data from the literature (Sherwood and Hirst, 2006). Then we fitted the value of the probability rate constant for O .-2 formation using data from (Kussmaul and Hirst, 2006).…”

Section: Comparison To Experimental Datamentioning

confidence: 99%

See 1 more Smart Citation

Modelling the redox imbalance in Dominant Optic Atrophy: the case of respiratory Complex I

2017

View full text Add to dashboard Cite

Dominant Optic Atrophy is a neuro-ophthalmic disease characterized by the degeneration of the optic nerves. As other neurodegenerative diseases, this pathology was associated with dysfunctional mitochondrial respiratory complexes and an increased production of Reactive Oxygen Species (ROS). Our objective is to create a mathematical model of the molecular mechanisms involved in the pathogenesis of Dominant Optic Atrophy in order to predict their evolution and give appropriated treatment based on in-silico analysis with physiological parameters from a specific patient. The first part of the work presented here concerns processes and feedback mechanisms of the whole dysfunctional mitochondrial system. The behaviour of the system is explained with a block diagram. In the second part, we present a detailed stochastic model of catalytic activity and ROS production of respiratory complex I. We developed the model using a Petri net formalism and a continuous-time Markov chains theory. The simulations were realized on Matlab and compared to kinetic data from the literature. Our model is able to reproduce the dynamics of the complex I system and to simulate observed behaviours of this system regarding ROS production.

show abstract

Investigation of the mechanism of proton translocation by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria: does the enzyme operate by a Q-cycle mechanism?

Cited by 42 publications

References 49 publications

Granzyme B-induced mitochondrial ROS are required for apoptosis

Granzyme B-induced mitochondrial ROS are required for apoptosis

Generation of Reactive Oxygen Species by Mitochondrial Complex I: Implications in Neurodegeneration

Modelling the redox imbalance in Dominant Optic Atrophy: the case of respiratory Complex I

Contact Info

Product

Resources

About