Upregulation of mitochondrial respiratory complex IV by estrogen receptor-β is critical for inhibiting mitochondrial apoptotic signaling and restoring cardiac functions following trauma–hemorrhage

ND1 subunit possesses the majority of the inhibitor binding domain of the human mitochondrial respiratory complex I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, that some metabolites from Annona muricata called acetogenins have important biological activities, such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine mitochondrial respiratory complex I by bis-tetrahydrofurans acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human mitochondrial respiratory complex I. In this work, we evaluate the in silico molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, quantum mechanical optimizations, molecular dynamics simulations and the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known mitochondrial respiratory complex I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger binding free energy compared to the rotenone complex. Detailed analysis of the binding free energy shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of the mitochondrial respiratory complex I.

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High intensity interval training induces dysregulation of mitochondrial respiratory complex and mitophagy in the hippocampus of middle-aged mice

Behavioural Brain Research ◽

10.1016/j.bbr.2021.113384 ◽

2021 ◽

pp. 113384

Author(s):

Yu Zhang ◽

Bo Liao ◽

Shuai Hu ◽

Shan-Yao Pan ◽

Gui-Ping Wang ◽

...

Keyword(s):

High Intensity ◽

Interval Training ◽

High Intensity Interval Training ◽

Middle Aged ◽

Respiratory Complex ◽

Aged Mice ◽

Mitochondrial Respiratory Complex ◽

High Intensity Interval ◽

Mitochondrial Respiratory

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Mutations in human nuclear genes encoding for subunits of mitochondrial respiratory complex I: the NDUFS4 gene

Gene ◽

10.1016/s0378-1119(01)00810-1 ◽

2002 ◽

Vol 286 (1) ◽

pp. 149-154 ◽

Cited By ~ 40

Author(s):

Vittoria Petruzzella ◽

Sergio Papa

Keyword(s):

Complex I ◽

Nuclear Genes ◽

Respiratory Complex ◽

Mitochondrial Respiratory Complex ◽

Genes Encoding ◽

Respiratory Complex I ◽

Mitochondrial Respiratory

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Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2004.03.016 ◽

2004 ◽

Vol 1658 (1-2) ◽

pp. 44-49 ◽

Cited By ~ 230

Author(s):

Guy C Brown ◽

Vilmante Borutaite

Keyword(s):

Nitric Oxide ◽

Complex I ◽

Respiratory Complex ◽

Mitochondrial Respiratory Complex ◽

Respiratory Complex I ◽

Mitochondrial Respiratory

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Abstract P281: Bcl-2 Limits Ischemia-Reperfusion Injury of the Naive Myocardium by Preserving Mitochondrial Integrity and Respiratory Complex Functionality and Is Modulated by PKCε

Circulation Research ◽

10.1161/res.109.suppl_1.ap281 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

David A Liem ◽

Jun Zhang ◽

Christopher Lotz ◽

Ding Wang ◽

Peipei Ping

Keyword(s):

Mitochondrial Permeability Transition ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Mass Spectrometry Analysis ◽

Myocardial Infarct Size ◽

Cardiac Mitochondria ◽

Respiratory Complex ◽

Mitochondrial Respiratory Complex ◽

Increased Susceptibility ◽

Mitochondrial Respiratory

Over-expression of Bcl-2 protects against myocardial ischemia/reperfusion (I/R) injury. Nevertheless, the participation of Bcl-2 in basal myocardium, and its subcellular targets under such conditions, remains elusive. Using a mouse line with an ablation of the Bcl-2 gene, we found that myocardial infarct size (IS) was exacerbated vs. wild type (WT) mice, demonstrating that Bcl-2 limit IS in basal I/R injury. The exacerbated IS in Bcl-2 KO was abolished by in vivo treatment with the selective Mitochondrial Permeability Transition (MPT) inhibitor cyclosporine A (10 mg/kg, iv) , while isolated cardiac mitochondria from Bcl-2 null mice exhibited increased matrix swelling in response to CaCl 2 , showing an increased susceptibility to MPT. However, recombinant Bcl-2 or PKCε were both sufficient to attenuate the increased susceptibility to MPT. Interestingly, spectrophotometric analysis of baseline activities of Mitochondrial Electron Transport Chain Complexes (ETC) I and V (but not of ETC II, III and IV), were increased in cardiac mitochondria from Bcl-2 null mice as compared to mitochondria from normal WT mice, demonstrating an altered mitochondrial respiratory complex functionality. In addition, immunoprecipitation with PKCε in AE-PKCε mouse hearts (i.e. mice with an increased activity of PKCε) followed by immunoblotting for Bcl-2, showed an 2-fold increased interaction between PKCε and Bcl-2. Similarly, immunoprecipitation with Phospho-Serine followed by immunoblotting for Bcl-2 indicated a 2-fold increased Serine residue phosphorylation of Bcl-2. Mass spectrometry analysis further showed that PKCε can phosporylate Bcl-2 at its Serine24 residue site in vitro, indicating that PKCε can directly interact and phosphorylate Bcl-2. These data suggest that Bcl-2 is pivotal in limiting IS in basal I/R injury by counteracting MPT and preserving mitochondrial respiratory complex functionality, and implicate a direct interaction and phosphorylation of Bcl-2 by PKCε in this process.

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