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2.
Cell Death Dis ; 7: e2238, 2016 05 26.
Article in English | MEDLINE | ID: mdl-27228353

ABSTRACT

Mitochondria alter their shape by undergoing cycles of fusion and fission. Changes in mitochondrial morphology impact on the cellular response to stress, and their interactions with other organelles such as the sarcoplasmic reticulum (SR). Inhibiting mitochondrial fission can protect the heart against acute ischemia/reperfusion (I/R) injury. However, the role of the mitochondrial fusion proteins, Mfn1 and Mfn2, in the response of the adult heart to acute I/R injury is not clear, and is investigated in this study. To determine the effect of combined Mfn1/Mfn2 ablation on the susceptibility to acute myocardial I/R injury, cardiac-specific ablation of both Mfn1 and Mfn2 (DKO) was initiated in mice aged 4-6 weeks, leading to knockout of both these proteins in 8-10-week-old animals. This resulted in fragmented mitochondria (electron microscopy), decreased mitochondrial respiratory function (respirometry), and impaired myocardial contractile function (echocardiography). In DKO mice subjected to in vivo regional myocardial ischemia (30 min) followed by 24 h reperfusion, myocardial infarct size (IS, expressed as a % of the area-at-risk) was reduced by 46% compared with wild-type (WT) hearts. In addition, mitochondria from DKO animals had decreased MPTP opening susceptibility (assessed by Ca(2+)-induced mitochondrial swelling), compared with WT hearts. Mfn2 is a key mediator of mitochondrial/SR tethering, and accordingly, the loss of Mfn2 in DKO hearts reduced the number of interactions measured between these organelles (quantified by proximal ligation assay), attenuated mitochondrial calcium overload (Rhod2 confocal microscopy), and decreased reactive oxygen species production (DCF confocal microscopy) in response to acute I/R injury. No differences in isolated mitochondrial ROS emissions (Amplex Red) were detected in response to Ca(2+) and Antimycin A, further implicating disruption of mitochondria/SR tethering as the protective mechanism. In summary, despite apparent mitochondrial dysfunction, hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction due to impaired mitochondria/SR tethering.


Subject(s)
GTP Phosphohydrolases/genetics , Mitochondrial Membrane Transport Proteins/genetics , Myocardial Infarction/genetics , Myocardial Reperfusion Injury/genetics , Myocytes, Cardiac/metabolism , Animals , Antimycin A/pharmacology , Calcium/metabolism , Calcium/pharmacology , GTP Phosphohydrolases/deficiency , Gene Expression , Mice , Mice, Knockout , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/ultrastructure , Mitochondrial Dynamics/drug effects , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/prevention & control , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Reactive Oxygen Species/metabolism , Sarcoplasmic Reticulum/drug effects , Sarcoplasmic Reticulum/metabolism
3.
Br J Pharmacol ; 172(8): 2074-84, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25393318

ABSTRACT

Mitochondria have long been known to be the gatekeepers of cell fate. This is particularly so in the response to acute ischaemia-reperfusion injury (IRI). Following an acute episode of sustained myocardial ischaemia, the opening of the mitochondrial permeability transition pore (MPTP) in the first few minutes of reperfusion, mediates cell death. Preventing MPTP opening at the onset of reperfusion using either pharmacological inhibitors [such as cyclosporin A (CsA) ] or genetic ablation has been reported to reduce myocardial infarct (MI) size in animal models of acute IRI. Interestingly, the endogenous cardioprotective intervention of ischaemic conditioning, in which the heart is protected against MI by applying cycles of brief ischaemia and reperfusion to either the heart itself or a remote organ or tissue, appears to be mediated through the inhibition of MPTP opening at reperfusion. Small proof-of-concept clinical studies have demonstrated the translatability of this therapeutic approach to target MPTP opening using CsA in clinical settings of acute myocardial IRI. However, given that CsA is a not a specific MPTP inhibitor, more novel and specific inhibitors of the MPTP need to be discovered - the molecular identification of the MPTP should facilitate this. In this paper, we review the role of the MPTP as a target for cardioprotection, the potential mechanisms underlying MPTP inhibition in the setting of ischaemic conditioning, and the translatability of MPTP inhibition as a therapeutic approach in the clinical setting.


Subject(s)
Ischemic Preconditioning, Myocardial , Mitochondrial Membrane Transport Proteins/antagonists & inhibitors , Myocardium/metabolism , Animals , Humans , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/prevention & control
4.
Cell Death Dis ; 5: e1082, 2014 Feb 27.
Article in English | MEDLINE | ID: mdl-24577080

ABSTRACT

Novel therapeutic targets are required to protect the heart against cell death from acute ischemia-reperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson's disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemia-reperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n=5, P<0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n=6, P<0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n=6 cells, P<0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1(L166P) and DJ-1(Cys106A) mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n≥7, P<0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection.


Subject(s)
Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/prevention & control , Myocardium/metabolism , Oncogene Proteins/metabolism , Adenosine Triphosphate/metabolism , Animals , Calcium/metabolism , Cell Death , Cell Line , Disease Models, Animal , Ischemic Preconditioning, Myocardial , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria, Heart/metabolism , Mitochondria, Heart/ultrastructure , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , Myocardial Infarction/genetics , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Myocardium/ultrastructure , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/ultrastructure , Oncogene Proteins/deficiency , Oncogene Proteins/genetics , Peroxiredoxins , Protein Deglycase DJ-1 , Transfection
5.
Br J Pharmacol ; 171(8): 1890-906, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24328763

ABSTRACT

Mitochondria are no longer considered to be solely the static powerhouses of the cell. While they are undoubtedly essential to sustaining life and meeting the energy requirements of the cell through oxidative phosphorylation, they are now regarded as highly dynamic organelles with multiple functions, playing key roles in cell survival and death. In this review, we discuss the emerging role of mitochondrial fusion and fission proteins, as novel therapeutic targets for treating a wide range of cardiovascular diseases.


Subject(s)
Cardiovascular Diseases/physiopathology , Mitochondrial Dynamics/physiology , Mitochondrial Proteins/physiology , Molecular Targeted Therapy/methods , Cardiovascular Diseases/metabolism , Cell Death/physiology , Cell Proliferation , Humans , Mitochondrial Proteins/metabolism , Models, Biological , Myocardium/metabolism
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