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Title: Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke

Highlights: • Rapamycin enhances mitophagy via increasing p62 translocation to the mitochondria. • Rapamycin attenuates brain ischemic damage and improves mitochondrial function. • The protection of rapamycin to mitochondrial is linked to enhanced mitophagy. - Abstract: Rapamycin has been demonstrated to exhibit neuroprotective functions via the activation of autophagy in a cerebral ischemia model. However, the involvement of mitophagy in this process and its contribution to the protection of mitochondrial function remains unknown. The present study explored the characteristics of mitophagy after cerebral ischemia and the effect of rapamycin on mitochondrial function. Male Sprague–Dawley rats underwent transient middle cerebral artery occlusion (tMCAO). Neurological deficits scores; infarct volumes; mitophagy morphology; and the levels of malondialdehyde (MDA), adenosine triphosphate (ATP) and mitochondrial membrane potentials (Δψm) were examined. The expression of LC3, Beclin-1 and p62 in the mitochondrial fraction combined with transmission electronic microscopy were used to explore mitophagic activity after ischemia. We also blocked autophagosome formation using 3-methyladenine (3-MA) to check the linkage between the mitochondrial protective effect of rapamycin and enhanced mitophagy. We observed that rapamycin significantly enhanced mitophagy, as evidenced by the increase in LC3-II and Beclin-1 expression in the mitochondria and p62 translocation to the mitochondria. Rapamycin reduced infarctmore » volume, improved neurological outcomes and inhibited mitochondrial dysfunction compared with the control animals (p < 0.05). However, these protective effects were reversed by 3-methyladenine treatment after rapamycin. The present study indicates that rapamycin treatment attenuates mitochondrial dysfunction following cerebral ischemia, which is linked to enhanced mitophagy.« less
Authors:
 [1] ;  [2] ;  [1] ;  [3] ;  [2] ;  [4] ;  [5] ;  [3] ;  [2] ;  [1]
  1. Department of Neurology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai 200233 (China)
  2. (China)
  3. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025 (China)
  4. Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030 (China)
  5. Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011 (China)
Publication Date:
OSTI Identifier:
22416260
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 444; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ATP; BRAIN; CEREBRAL ARTERIES; DMSO; ISCHEMIA; MEMBRANES; MICROTUBULES; MITOCHONDRIA; MORPHOLOGY; PROTEINS; RATS; TRANSLOCATION; TRANSMISSION ELECTRON MICROSCOPY; VISIBLE RADIATION