Reperfusion promotes mitochondrial biogenesis following focal cerebral ischemia in rats

PLoS One. 2014 Mar 25;9(3):e92443. doi: 10.1371/journal.pone.0092443. eCollection 2014.


Background and purpose: Reperfusion after transient cerebral ischemia causes severe damage to mitochondria; however, little is known regarding the continuous change in mitochondrial biogenesis during reperfusion. Mitochondrial biogenesis causes an increase in the individual mitochondrial mass of neurons and maintains their aerobic set-point in the face of declining function. The aim of this study was to examine mitochondrial biogenesis in the cortex during reperfusion following focal cerebral ischemia.

Methods: Male Wistar rats were subjected to transient focal cerebral ischemia. The relative amount of cortical mitochondrial DNA was analyzed using quantitative real-time PCR at 0 h, 24 h, 72 h, and 7 d after reperfusion. Three critical transcriptional regulators of mitochondrial biogenesis were measured by semi-quantitative reverse-transcription PCR. The protein expression of cytochrome C oxidase subunits I and IV was detected by Western blotting.

Results: Evidence of increased mitochondrial biogenesis was observed after reperfusion. The cortical mitochondrial DNA content increased after 24 h, peaked after 72 h, and maintained a high level for 7 d. The cortical expression of three critical genes for the transcriptional regulation of mitochondrial biogenesis, namely, peroxisome proliferator-activated receptor coactivator-1α, nuclear respiratory factor-1, and mitochondrial transcription factor A, also increased at 24 h and 72 h. The expression of peroxisome proliferator-activated receptor coactivator-1α returned to the baseline level at 7 d, but two other factors maintained higher levels compared with the controls. Moreover, the expression of cytochrome C oxidase subunits I and IV was increased in the cortex.

Conclusions: These results indicate that reperfusion increased mitochondrial biogenesis following focal cerebral ischemia, and this tendency was exacerbated as the reperfusion time was extended. Reperfusion-induced mitochondrial biogenesis was mediated through up-regulation of critical transcriptional regulators of mitochondrial biogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Citrate (si)-Synthase / genetics
  • Citrate (si)-Synthase / metabolism
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • Male
  • Mitochondrial Turnover / physiology*
  • RNA, Messenger / genetics
  • Rats
  • Rats, Wistar
  • Real-Time Polymerase Chain Reaction
  • Reperfusion*
  • Reverse Transcriptase Polymerase Chain Reaction


  • DNA, Mitochondrial
  • RNA, Messenger
  • Electron Transport Complex IV
  • Citrate (si)-Synthase

Grants and funding

This project was supported by grants from the Natural Science Foundation of China (No. 81271456) and the Nature Science Foundation of Heilongjiang Province (ZD201017). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.