Acute mental stress induces mitochondrial bioenergetic crisis and hyper-fission along with aberrant mitophagy in the gut mucosa in rodent model of stress-related mucosal disease

Autor: Uday Bandyopadhyay, Somnath Mazumder, Souvik Sarkar, Shubhra Jyoti Saha, Chinmoy Banerjee, Rudranil De, Shiladitya Nag, Debanjan Saha, Subhashis Debsharma, Asim Azhar Siddiqui
Rok vydání: 2017
Předmět:
0301 basic medicine
Pathology
Receptors
Cytoplasmic and Nuclear
Mitochondrion
medicine.disease_cause
Mitochondrial Dynamics
Biochemistry
Parkin
Rats
Sprague-Dawley
chemistry.chemical_compound
Adenosine Triphosphate
Piperidines
Superoxides
Mitochondrial Precursor Protein Import Complex Proteins
Mitophagy
bcl-2-Associated X Protein
Superoxide
Stomach
NF-kappa B
Mitochondria
Cell biology
Cold Temperature
Mifepristone
Antipsychotic Agents
Mitochondrial DNA
medicine.medical_specialty
Ubiquitin-Protein Ligases
Receptors
Cell Surface
PINK1
Biology
Mitochondrial Proteins
Immobilization
03 medical and health sciences
Organophosphorus Compounds
Receptors
Glucocorticoid
Physiology (medical)
Intensive care
medicine
Animals
Inflammation
Electron Transport Complex I
Membrane Transport Proteins
Oxidative Stress
030104 developmental biology
Gene Expression Regulation
chemistry
Gastric Mucosa
Corticosterone
Protein Kinases
Stress
Psychological
Oxidative stress
Zdroj: Free Radical Biology and Medicine. 113:424-438
ISSN: 0891-5849
DOI: 10.1016/j.freeradbiomed.2017.10.009
Popis: Psychological stress, depression and anxiety lead to multiple organ dysfunctions wherein stress-related mucosal disease (SRMD) is common to people experiencing stress and also occur as a side effect in patients admitted to intensive care units; however the underlying molecular aetiology is still obscure. We report that in rat-SRMD model, cold restraint-stress severely damaged gut mitochondrial functions to generate superoxide anion (O2•-), depleted ATP and shifted mitochondrial fission-fusion dynamics towards enhanced fission to induce mucosal injury. Activation of mitophagy to clear damaged and fragmented mitochondria was evident from mitochondrial translocation of Parkin and PINK1 along with enhanced mitochondrial proteome ubiquitination, depletion of mitochondrial DNA copy number and TOM 20. However, excess and sustained accumulation of O2•--generating defective mitochondria overpowered the mitophagic machinery, ultimately triggering Bax-dependent apoptosis and NF-κB-intervened pro-inflammatory mucosal injury. We further observed that stress-induced enhanced serum corticosterone stimulated mitochondrial recruitment of glucocorticoid receptor (GR), which contributed to gut mitochondrial dysfunctions as documented from reduced ETC complex 1 activity, mitochondrial O2•- accumulation, depolarization and hyper-fission. GR-antagonism by RU486 or specific scavenging of mitochondrial O2•- by a mitochondrially targeted antioxidant mitoTEMPO ameliorated stress-induced mucosal damage. Gut mitopathology and mucosal injury were also averted when the perception of mental stress was blocked by pre-treatment with a sedative or antipsychotic. Altogether, we suggest the role of mitochondrial GR-O2•--fission cohort in brain-mitochondria cross-talk during acute mental stress and advocate the utilization of this pathway as a potential target to prevent mitochondrial unrest and gastropathy bypassing central nervous system.
Databáze: OpenAIRE
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