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Hyperglycemia Alters Mitochondrial Fission and Fusion Proteins in Mice Subjected to Cerebral Ischemia and Reperfusion

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Abstract

Preischemic hyperglycemia exacerbates brain damage caused by cerebral ischemia. In the present experiment, we studied the effects of preischemic hyperglycemia on protein markers that are related to mitochondrial fission and fusion, mitochondrial biogenesis, and autophagy in mice subjected to 30-min transient focal ischemia. The fission proteins dynamin-related protein 1 (Drp1) and fission 1 (Fis1), fusion proteins optic atrophy 1 (Opa1) and mitofusin 2 (Mfn2), mitochondrial biogenesis regulators nuclear respiratory factor 1 (NRF1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and autophagy marker beclin 1 and microtubule-associated protein light chain 3 (LC3) were analyzed in control, 30 min middle cerebral artery occlusion (MCAO) plus 6-, 24-, and 72 h of reperfusion in normo- and hyperglycemic conditions. Cerebral ischemia increased the levels of Drp1 and decreased Fis1 after reperfusion. Preischemic hyperglycemia further augmented the increase of Drp1 and induced elevation in Fis1. Ischemia inhibited the levels of Opa1 and Mfn2 and hyperglycemia further decreased the level of Opa1. Further, NRF1 increased after reperfusion in both normo- and hyperglycemic animals. However, such increase was caused by reperfusion rather than glucose level. Finally, ischemia increased beclin 1 level at 6 and 24 h of reperfusion and hyperglycemia further increased the beclin 1 level and caused LC3-II increase as well. Hyperglycemia enhances the ischemia-induced mitochondrial dynamic imbalance towards fission that may favor mitochondrial fragmentation and subsequent damage. Hyperglycemia elevated autophagy markers may represent an adapting reaction to the severe damage incurred in hyperglycemic animals or a third pathway of cell death.

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Abbreviations

CCA:

Common carotid artery

Drp1:

Dynamin-related protein 1

Mfn2:

Mitofusin 2

ICA:

Internal carotid artery

LC3:

Microtubule-associated protein light chain 3

MCA:

Middle cerebral artery

MCAO:

Middle cerebral artery occlusion

NRF1:

Nuclear respiratory factor 1

Opa1:

Optic atrophy 1

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

Tfam:

Transcription factor A

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Acknowledgments

This work is supported by a grant from the National Institute of Health to PAL (7R01DK075476). The BRITE is partially funded by the Golden Leaf Foundation.

Conflict of Interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, BRITE Building 2025, 302 East Lawson Street, Durham, NC, 27707, USA

    Santosh Kumari, Lavita Anderson, Stephanie Farmer, Suresh L. Mehta & P. Andy Li

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  1. Santosh Kumari
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Correspondence to P. Andy Li.

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Kumari, S., Anderson, L., Farmer, S. et al. Hyperglycemia Alters Mitochondrial Fission and Fusion Proteins in Mice Subjected to Cerebral Ischemia and Reperfusion. Transl. Stroke Res. 3, 296–304 (2012). https://doi.org/10.1007/s12975-012-0158-9

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