Elucidating Mitochondrial Electron Transport Chain Supercomplexes in the Heart During Ischemia–Reperfusion

Jang, Sehwan; Lewis, Taber S.; Powers, Corey; Khuchua, Zaza; Baines, Christopher P.; Wipf, Peter; Javadov, Sabzali

doi:10.1089/ars.2016.6635

Cited by 84 publications

(90 citation statements)

References 69 publications

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“…Mitochondrial SCs were analyzed by blue-native polyacrylamide gel electrophoresis (BN-PAGE) as previously described with modifications [13,24,25]. Briefly, 120 μg of mitochondrial proteins was dissolved in 100 μL of solubilization buffer (50 mM NaCl, 50 mM imidazole-HCl, 2 mM 6-aminohexanoic acid, 1 mM EDTA) supplemented with 4 μL of 20% digitonin, 1 μL protease and phosphatase inhibitor cocktails (Sigma-Aldrich), and 25 U of Benzonase ® .…”

Section: Methodsmentioning

confidence: 99%

“…Depletion of cardiolipin [30,31] and degradation of SCs [14] were found in animal models of heart failure. Loss of tafazzin, an enzyme responsible for cardiolipin remodeling, induced a 40% loss of mature cardiolipin (tetralinoleyl-cardiolipin) [32], and disintegration of SCs [25]. Degradation of SCs and oxidation of cardiolipin induced by ischemia-reperfusion in rat hearts were prevented in the presence of XJB-5-131, a mitochondria-targeted electron scavenger [25].…”

Section: Introductionmentioning

confidence: 99%

“…Our recent studies showed that ROS production and PTP-induced mitochondrial swelling can play a causative role in SC degradation in response to oxidative stress induced by ischemia-reperfusion in rat hearts [25]. In this study, we evaluated the possible relationship between mitochondrial swelling, ROS production and respirasome integrity.…”

Section: Introductionmentioning

confidence: 99%

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Association between ROS production, swelling and the respirasome integrity in cardiac mitochondria

Jang

Javadov

2017

Archives of Biochemistry and Biophysics

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Although mitochondrial Ca2+ overload and ROS production play a critical role in mitochondria-mediated cell death, a cause-effect relationship between them remains elusive. This study elucidated the crosstalk between mitochondrial swelling, ROS production, and electron transfer chain (ETC) supercomplexes in rat heart mitochondria in response to Ca2+ and tert-butyl hydroperoxide (TBH), a lipid-soluble organic peroxide. Results showed that ROS production induced by TBH was significantly increased in the presence of Ca2+ in a dose-dependent manner. TBH markedly inhibited the state 3 respiration rate with no effect on the mitochondrial swelling. Ca2+ exerted a slight effect on mitochondrial respiration that was greatly aggravated by TBH. Analysis of supercomplexes revealed a minor difference in the presence of TBH and/or Ca2+. However, incubation of mitochondria in the presence of high Ca2+ (1 mM) or inhibitors of ETC complexes (rotenone and antimycin A) induced disintegration of the main supercomplex, respirasome. Thus, PTP-dependent swelling of mitochondria solely depends on Ca2+ but not ROS. TBH has no effect on the respirasome while Ca2+ induces disintegration of the supercomplex only at a high concentration. Intactness of individual ETC complexes I and III is important for maintenance of the structural integrity of the respirasome.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association between ROS production, swelling and the respirasome integrity in cardiac mitochondria

Jang

Javadov

2017

Archives of Biochemistry and Biophysics

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“…ROS are released from mitochondria into respiratory complexes called supercomplexes, functional aggregates of the electron transport system that are essential for normal electron flux 48–51 . Fewer respiratory supercomplexes are formed in the setting of acute 52 and chronic 53,54 cardiac pathologies. Since ROS production seems to be inversely related to supercomplex formation 55 , the loss of supercomplexes might be directly linked to augmented ROS production in a ‘vicious cycle’.…”

Section: Targeting the Mitochondriamentioning

confidence: 99%

“…Direct scavengers that lessen mitochondrial radical accumulation, such as the scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO; targeted to mitochondria via gramicidin XJB-5-131 (REFS 52,56)) or triphenylphosphonium (Mito-TEMPO) 57 are cardioprotective in preclinical models. The hydroxyl scavenger 3--methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) 58 and several newer superoxide dismutase mimetics such as EUK8/EUK134 (REFS 59–61), M40403 (REF.…”

Section: Targeting the Mitochondriamentioning

confidence: 99%

New and revisited approaches to preserving the reperfused myocardium

et al. 2017

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Early coronary artery reperfusion improves outcomes for patients with ST-segment elevation myocardial infarction (STEMI), but morbidity and mortality after STEMI remain unacceptably high. The primary deficits seen in these patients include inadequate pump function, owing to rapid infarction of muscle in the first few hours of treatment, and adverse remodelling of the heart in the months that follow. Given that attempts to further reduce myocardial infarct size beyond early reperfusion in clinical trials have so far been disappointing, effective therapies are still needed to protect the reperfused myocardium. In this Review, we discuss several approaches to preserving the reperfused heart, such as therapies that target the mechanisms involved in mitochondrial bioenergetics, pyroptosis, and autophagy, as well as treatments that harness the cardioprotective properties of inhaled anaesthetic agents. We also discuss potential therapies focused on correcting the no-reflow phenomenon and its effect on healing and adverse left ventricular remodelling.

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Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity

Yuan

Chen

et al. 2021

FEBS Open Bio

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Hypoxia is a risk factor for Alzheimer's disease (AD). Besides, mitochondrial fission is increased in response to hypoxia. In this study, we sought to investigate whether hypoxia‐induced mitochondrial fission plays a critical role in regulating amyloid‐β (Aβ) production. Hypoxia significantly activated extracellular signal‐regulated kinase (ERK), increased phosphorylation of dynamin‐related protein 1 (Drp1) at serine 616, and decreased phosphorylation of Drp1 at serine 637. Importantly, hypoxia triggered mitochondrial dysfunction, elevated β‐secretase 1 (BACE1) and γ‐secretase activities, and promoted Aβ accumulation in HEK293 cells transfected with β‐amyloid precursor protein (APP) plasmid harboring the Swedish and Indiana familial Alzheimer's disease mutations (APPSwe/Ind HEK293 cells). Then, we investigated whether the ERK inhibitor PD325901 and Drp1 inhibitor mitochondrial division inhibitor‐1 (Mdivi‐1) would attenuate hypoxia‐induced mitochondrial fission and Aβ generation in APPSwe/Ind HEK293 cells. PD325901 and Mdivi‐1 inhibited phosphorylation of Drp1 at serine 616, resulting in reduced mitochondrial fission under hypoxia. Furthermore, hypoxia‐induced mitochondrial dysfunction, BACE1 activation, and Aβ accumulation were downregulated by PD325901 and Mdivi‐1. Our data demonstrate that hypoxia induces mitochondrial fission, impairs mitochondrial function, and facilitates Aβ generation. The ERK–Drp1 signaling pathway is partly involved in the hypoxia‐induced Aβ generation by regulating mitochondrial fission and BACE1 activity. Therefore, inhibition of hypoxia‐induced mitochondrial fission may prevent or slow the progression of AD.

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Elucidating Mitochondrial Electron Transport Chain Supercomplexes in the Heart During Ischemia–Reperfusion

Cited by 84 publications

References 69 publications

Association between ROS production, swelling and the respirasome integrity in cardiac mitochondria

Association between ROS production, swelling and the respirasome integrity in cardiac mitochondria

New and revisited approaches to preserving the reperfused myocardium

Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity

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