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1.
FEBS J ; 288(11): 3547-3569, 2021 06.
Article in English | MEDLINE | ID: mdl-33340237

ABSTRACT

Myocardial ischemia/reperfusion (I/R) injury is a frequent perioperative threat, with numerous strategies developed to limit and/or prevent it. One interesting axis of research is the anesthetic preconditioning (APc) agent's hypothesis (such as sevoflurane, SEV). However, APc's mode of action is still poorly understood and volatile anesthetics used as preconditioning agents are often not well suited in clinical practice. Here, in vitro using H9C2 cells lines (in myeloblast state or differentiated toward cardiomyocytes) and in vivo in mice, we identified that SEV-induced APc is mediated by a mild induction of reactive oxygen species (ROS) that activates Akt and induces the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL), therefore protecting cardiomyocytes from I/R-induced death. Furthermore, we extended these results to human cardiomyocytes (derived from induced pluripotent stem - IPS - cells). Importantly, we demonstrated that this protective signaling pathway induced by SEV could be stimulated using the antidiabetic agent metformin (MET), suggesting the preconditioning properties of MET. Altogether, our study identified a signaling pathway allowing APc of cardiac injuries as well as a rational for the use of MET as a pharmacological preconditioning agent to prevent I/R injuries.


Subject(s)
Apoptosis/drug effects , Myocardial Reperfusion Injury/drug therapy , Reperfusion Injury/drug therapy , bcl-X Protein/genetics , Animals , Cell Survival/drug effects , Humans , Hypoglycemic Agents/pharmacology , Metformin/pharmacology , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/pathology , Myocytes, Cardiac/drug effects , Rats , Reactive Oxygen Species/metabolism , Reperfusion Injury/genetics , Reperfusion Injury/pathology , Sevoflurane/pharmacology , Signal Transduction/drug effects
3.
Cell Rep ; 20(12): 2846-2859, 2017 Sep 19.
Article in English | MEDLINE | ID: mdl-28930681

ABSTRACT

Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. Because the main known regulators of mitophagy are frequently inactivated in cancer cells, the mechanisms that regulate mitophagy in cancer cells are not fully understood. Here, we identified an E3 ubiquitin ligase (ARIH1/HHARI) that triggers mitophagy in cancer cells in a PINK1-dependent manner. We found that ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal via autophagy. Importantly, ARIH1 is widely expressed in cancer cells, notably in breast and lung adenocarcinomas; ARIH1 expression protects against chemotherapy-induced death. These data challenge the view that the main regulators of mitophagy are tumor suppressors, arguing instead that ARIH1-mediated mitophagy promotes therapeutic resistance.


Subject(s)
Antineoplastic Agents/pharmacology , Carrier Proteins/metabolism , Mitophagy , Neoplasms/metabolism , Ubiquitin-Protein Ligases/metabolism , Autophagy/drug effects , Cell Death/drug effects , Cell Line, Tumor , Cytoprotection/drug effects , HeLa Cells , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Mitophagy/drug effects , Neoplasms/pathology , Protein Kinases/metabolism , Protein Stability/drug effects
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