Mitochondrial Proton Leak Plays a Critical Role in Pathogenesis of Cardiovascular Diseases

Cheng, Jiali; Nanayakkara, Gayani; Shao, Ying; Cueto, Ramón; Wang, Luqiao; Yang, William Y.; Tian, Ye; Wang, Hong; Yang, Xiaofeng

doi:10.1007/978-3-319-55330-6_20

Cited by 129 publications

(108 citation statements)

References 53 publications

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“…In this context, our findings are in line with several reports in the literature that showed atypical overactivity of mitochondrial ETC complexes I and IV in different cells and tissues of ASD patients 28‐32 . Interestingly, changes of mitochondrial respiration in ASD fibroblasts are associated with an increased proton leak, a phenomenon that lead to the incomplete coupling of substrate oxygen and ATP generation but, at the same time, is a protective mechanism adopted for mitigating mitochondrial ROS production 33 . Higher proton leak was observed also in ASD lymphoblastoid cells, where it was driven by an upregulated expression of uncoupling proteins such as mitochondrial uncoupling protein 2 (UCP2) 22,24 …”

Section: Discussionsupporting

confidence: 92%

Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder

et al. 2020

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JoussefHayek and Giuseppe Valacchi contributed equally to this work.Abbreviations: 4-HNE, 4-hydroxynonenal; ASD, autism spectrum disorder; ATP5A, ATP synthase subunit alpha, mitochondrial; COX4, cytochrome c oxidase subunit 4 isoform 1, mitochondrial; DMEM, Dulbecco's Modification of Eagle's Medium; DRP1, dynamin-1-like protein; ECAR, extracellular acidification rate; ETC, electron transport chain; FBS, fetal bovine serum; FCCP, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; FIS1, mitochondrial fission 1 protein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GSH, glutathione; H 2 O 2 , hydrogen peroxide; HBSS, Hanks' balanced salt solution; HDCA1, histone deacetylase 1; HDL, high-density lipoproteins; HO-1, heme oxygenase 1; MFN1, mitofusin-1; MFN2, mitofusin-2; NADPH, nicotinamide adenine dinucleotide phosphate; NDUFB8, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial; NFκB, nuclear factor NF-kappa-B; NOX, NADPH (Nicotinamide adenine dinucleotide phosphate) oxidase; NPBI, nonprotein-bound iron; NQO1, NAD(P)H quinone dehydrogenase 1; Nrf2, nuclear factor erythroid 2-related factor 2; OCR, oxygen consuming ratio; OPA1, dynamin-like 120 kDa protein, mitochondrial; Parkin, E3 ubiquitin-protein ligase parkin; PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; PINK1, serine/threonine-protein kinase PINK1, mitochondrial; PMA, phorbol myristate acetate; PON-1, paraoxonase-1; PVDF, polyvinylidene difluoride; RFU, relative fluorescence units; RIPA, radio-immunoprecipitation assay; RLU, relative luminescence units; ROS, reactive oxygen species; SDHA, succinate dehydrogenase complex flavoprotein subunit A; SIRT3, sirtuin 3; SOD, superoxide dismutase; TBS-T, tris-buffered saline, 0.1% Tween 20; TEM, transmission electron microscopy; TOMM20, translocase of outer mitochondrial membrane 20; TRX, thioredoxin; TXNIP, thioredoxin-interacting protein; UCP2, mitochondrial uncoupling protein 2; UQCRC2, cytochrome b-c1 complex subunit 2, mitochondrial. AbstractAutism spectrum disorder (ASD) has been hypothesized to be a result of the interplay between genetic predisposition and increased vulnerability to early environmental insults. Mitochondrial dysfunctions appear also involved in ASD pathophysiology, but the mechanisms by which such alterations develop are not completely understood.Here, we analyzed ASD primary fibroblasts by measuring mitochondrial bioenergetics, ultrastructural and dynamic parameters to investigate the hypothesis that defects in these pathways could be interconnected phenomena responsible or consequence for the redox imbalance observed in ASD. High levels of 4-hydroxynonenal protein adducts together with increased NADPH (nicotinamide adenine dinucleotide phosphateoxidase) activity and mitochondrial superoxide production coupled with a compromised antioxidant response guided by a defective Nuclear Factor Erythroid 2-Related Factor 2 pathway confirmed an unbalanced redox homeostasis in ASD.Moreover, ASD fibroblasts showed overactive mitochondrial bioenerget...

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Section: Discussionsupporting

confidence: 92%

Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder

et al. 2020

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“…Indeed, we identified increased baseline respiration in AMs of COPD patients ( Figure 5I), which reflects an elevated energy demand. We also found a significant increase in proton leakage in AMs of COPD patients, which is indicative for increased ROS production in COPD (Boukhenouna et al, 2018;Cheng et al, 2017;McGuinness and Sapey, 2017) and mitochondrial dysfunction (Eapen et al, 2019;Hoffmann et al, 2019;Ng Kee Kwong et al, 2017).…”

Section: Copd Leads To Major Changes In Most Am States 12supporting

confidence: 51%

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Baßler

Fujii

Kapellos

et al. 2020

Preprint

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Despite the epidemics of chronic obstructive pulmonary disease (COPD), the cellular and molecular mechanisms of this disease are far from being understood. Here, we characterize and classify the cellular composition within the alveolar space and peripheral blood of COPD patients and control donors using a clinically applicable single-cell RNA-seq technology corroborated by advanced computational approaches for: machine learning-based cell-type classification, identification of differentially expressed genes, prediction of metabolic changes, and modeling of cellular trajectories within a patient cohort. These high-resolution approaches revealed: massive transcriptional plasticity of macrophages in the alveolar space with increased levels of invading and proliferating cells, loss of MHC expression, reduced cellular motility, altered lipid metabolism, and a metabolic shift reminiscent of mitochondrial dysfunction in COPD patients. Collectively, single-cell omics of multi-tissue samples was used to build the first cellular and molecular framework for COPD pathophysiology as a prerequisite to develop molecular biomarkers and causal therapies against this deadly disease.

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“…Therefore, the mitochondrial electrochemical gradient or membrane potential (ΔΨ m ) results from the balance between H + extrusion and H + dissipation and may be used as an index of the efficiency of mitochondrial respiration and/or degree of respiratory (un)coupling. Several factors, such as high energy expenditure, the presence of pharmacological uncouplers (such as dinitrophenol or FCCP) or the expression of uncoupling proteins may contribute to the dissipation of ΔΨ m which, in turn, reduces ROS production [72]. Under ischemic conditions, lack of O 2 stops the activity of the electron transport chain through the respiratory complexes, and mitochondria progressively depolarize mainly because H + extrusion to the intermembrane space is interrupted and H + flows back into the mitochondrial matrix through ATP synthase and other uncoupling proteins [360].…”

Section: Involvement Of Mitochondria In Cardiomyocyte Injurymentioning

confidence: 99%

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

et al. 2018

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Mitochondrial Proton Leak Plays a Critical Role in Pathogenesis of Cardiovascular Diseases

Cited by 129 publications

References 53 publications

Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder

Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

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