Hyperglycemia abolished Drp-1-mediated mitophagy at the early stage of cerebral ischemia.

Affiliation

Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China. Electronic address: [Email]

Abstract

Exposure to hyperglycemia after cerebral ischemia exacerbates cerebral damage; however, little is known regarding the mechanism. In this study, we focused on the relationship between post-ischemic hyperglycemia and mitochondrial homeostasis at the early stage of ischemia (within the 6 h clinical therapeutic window for thrombolysis). Permanent cerebral ischemia was induced by middle cerebral artery occlusion (pMCAO) for 1, 3, and 6 h. We first elucidated the role of post-ischemic hyperglycemia on mitochondria-mediated injury by testing reactive oxygen species generation, cyt-c release, and caspase-3 activation. Next, we analyzed mitochondrial homeostasis by testing the protein levels related to fission, fusion, biogenesis and elimination. The results showed that hyperglycemia further augmented the mitochondria-mediated injury induced by pMCAO. No significant differences of Fis1, Opa1 and Mfn2 were observed at each time point. There is no significant influence on these three proteins after hyperglycemia in rats of the experimental group compared to their counterparts in the control group. The translocation of the fission protein Drp1 to the mitochondrial outer-membrane increased at 1 h after pMCAO and later steadily decreased over time in normal animals. However, hyperglycemia inhibited both the levels of Drp1 in the cytoplasm and mitochondria. Moreover, hyperglycemia inhibited mitophagy induced by pMCAO at 1 h, although the overall autophagy was increased. In conclusion, pMCAO transiently induced the mitochondrial fission and their elimination by mitophagy. However, hyperglycemia abolished this adaptation reaction of the mitochondria and thus resulted in the accumulation of damaged mitochondria and subsequent damage. Our findings help to refine our understanding of the role of post-ischemic hyperglycemia in brain ischemic injury.

Keywords

Hyperglycemia,Mitochondrial autophagy,Mitochondrial homeostasis,Permanent cerebral ischemia,