Computational Modeling Analysis of Generation of Reactive Oxygen Species by Mitochondrial Assembled and Disintegrated Complex II

Markevich, L. N.; Hoek, Jan B.

doi:10.3389/fphys.2020.557721

Cited by 13 publications

(13 citation statements)

References 19 publications

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“…complex I [46] and the UQCRC2 (Cytochrome b-c1 complex subunit 2) subunit of complex III [47], whereas no changes were detected in the level of the SDBH (Succinate dehydrogenase [ubiquinone] iron-sulfur subunit) of complex II [48], the COX IV (Cytochrome c oxidase subunit 4 isoform 1) subunit of complex IV [49], and the F1-beta-subunit of the mitochondrial ATP synthase of complex V [50] (Fig. 4A).…”

Section: Sos1 Ablation Is Linked To Specific Alterations Of Components Of Mitochondrial Respiratory Complexes and Their Assembly In Supermentioning

confidence: 99%

Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis

et al. 2021

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SOS1 ablation causes specific defective phenotypes in MEFs including increased levels of intracellular ROS. We showed that the mitochondria-targeted antioxidant MitoTEMPO restores normal endogenous ROS levels, suggesting predominant involvement of mitochondria in generation of this defective SOS1-dependent phenotype. The absence of SOS1 caused specific alterations of mitochondrial shape, mass, and dynamics accompanied by higher percentage of dysfunctional mitochondria and lower rates of electron transport in comparison to WT or SOS2-KO counterparts. SOS1-deficient MEFs also exhibited specific alterations of respiratory complexes and their assembly into mitochondrial supercomplexes and consistently reduced rates of respiration, glycolysis, and ATP production, together with distinctive patterns of substrate preference for oxidative energy metabolism and dependence on glucose for survival. RASless cells showed defective respiratory/metabolic phenotypes reminiscent of those of SOS1-deficient MEFs, suggesting that the mitochondrial defects of these cells are mechanistically linked to the absence of SOS1-GEF activity on cellular RAS targets. Our observations provide a direct mechanistic link between SOS1 and control of cellular oxidative stress and suggest that SOS1-mediated RAS activation is required for correct mitochondrial dynamics and function.

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Section: Sos1 Ablation Is Linked To Specific Alterations Of Components Of Mitochondrial Respiratory Complexes and Their Assembly In Supermentioning

confidence: 99%

Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis

et al. 2021

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“…In addition, deletion of CPNS1 also decreases ROS generation when succinate + rotenone is used as substrate. This latter result indicates that deletion of CPNS1 also decreases ROS generation from complex II 67 and likely also from complex III 65 in that the reverse electron flow is blocked by rotenone 34 , 63 , 64 . The reverse electron flow-induced ROS generation contributes to cardiac injury during ischemia–reperfusion 64 .…”

Section: Discussionmentioning

confidence: 84%

Calpain-mediated protein targets in cardiac mitochondria following ischemia–reperfusion

Thompson

et al. 2022

Sci Rep

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Calpain 1 and 2 (CPN1/2) are calcium-dependent cysteine proteases that exist in cytosol and mitochondria. Pharmacologic inhibition of CPN1/2 decreases cardiac injury during ischemia (ISC)–reperfusion (REP) by improving mitochondrial function. However, the protein targets of CPN1/2 activation during ISC–REP are unclear. CPN1/2 include a large subunit and a small regulatory subunit 1 (CPNS1). Genetic deletion of CPNS1 eliminates the activities of both CPN1 and CPN2. Conditional cardiomyocyte specific CPNS1 deletion mice were used in the present study to clarify the role of CPN1/2 activation in mitochondrial damage during ISC–REP with an emphasis on identifying the potential protein targets of CPN1/2. Isolated hearts from wild type (WT) or CPNS1 deletion mice underwent 25 min in vitro global ISC and 30 min REP. Deletion of CPNS1 led to decreased cytosolic and mitochondrial calpain 1 activation compared to WT. Cardiac injury was decreased in CPNS1 deletion mice following ISC–REP as shown by the decreased infarct size compared to WT. Compared to WT, mitochondrial function was improved in CPNS1 deletion mice following ischemia–reperfusion as shown by the improved oxidative phosphorylation and decreased susceptibility to mitochondrial permeability transition pore opening. H2O2 generation was also decreased in mitochondria from deletion mice following ISC–REP compared to WT. Deletion of CPNS1 also resulted in less cytochrome c and truncated apoptosis inducing factor (tAIF) release from mitochondria. Proteomic analysis of the isolated mitochondria showed that deletion of CPNS1 increased the content of proteins functioning in regulation of mitochondrial calcium homeostasis (paraplegin and sarcalumenin) and complex III activity. These results suggest that activation of CPN1 increases cardiac injury during ischemia–reperfusion by impairing mitochondrial function and triggering cytochrome c and tAIF release from mitochondria into cytosol.

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“…While several mitochondrial ROS models exist 41,42,[53][54][55][56] , none can reproduce the wide variety of available mitochondrial bioenergetic data quantitatively and consistently. These models either lack the biophysical details to simulate the enzymatic reactions associated with both high and low electron flux regimes 42,56 or exclude complex II as a ROS-producing component 53 .…”

Section: Discussion 1 Model Predictions Of Site-specific Ros From the Ets Complexesmentioning

confidence: 99%

Identifying Site-specific Superoxide and Hydrogen Peroxide Production Rates from the Mitochondrial Electron Transport System Using a Computational Strategy

Duong

Levitsky

Dessinger

et al. 2021

Preprint

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Mitochondrial reactive oxygen species (ROS) play important roles in cellular signaling; however, certain pathological conditions such as ischemia/reperfusion (I/R) injury disrupt ROS homeostasis and contribute to cell death. A major impediment to developing therapeutic measures against oxidative stress induced cellular damage is the lack of a quantitative framework to identify the specific sources and regulatory mechanisms of mitochondrial ROS production. We developed a thermodynamically consistent, mass-and-charge balanced, kinetic model of mitochondrial ROS homeostasis focused on redox sites of electron transport chain complexes I, II, and III. The model was calibrated and validated using comprehensive data sets relevant to ROS homeostasis. The model predicts that complex I ROS production dominates other sources under conditions favoring a high membrane potential with elevated NADH and QH2 levels. In general, complex I contributes to significant levels of ROS production under pathological conditions, while complexes II and III are responsible for basal levels of ROS production, especially when QH2 levels are elevated. The model also reveals that hydrogen peroxide production by complex I underlies the non-linear relationship between ROS emission and O2 at low O2 concentrations. Lastly, the model highlights the need to quantify scavenging system activity under different conditions to establish a complete picture of mitochondrial ROS homeostasis. In summary, we describe the individual contributions of the ETS complex redox sites to total ROS emission in mitochondria respiring under various combinations of NADH- and Q-linked respiratory fuels under varying work rates.

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Computational Modeling Analysis of Generation of Reactive Oxygen Species by Mitochondrial Assembled and Disintegrated Complex II

Cited by 13 publications

References 19 publications

Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis

Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis

Calpain-mediated protein targets in cardiac mitochondria following ischemia–reperfusion

Identifying Site-specific Superoxide and Hydrogen Peroxide Production Rates from the Mitochondrial Electron Transport System Using a Computational Strategy

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