Abstract
Background and PurposeReperfusion 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.MethodsMale 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.ResultsEvidence 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.ConclusionsThese 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.
Highlights
Essential roles of mitochondria include regulating energy metabolism, generating reactive oxygen species (ROS), and mediating apoptosis in response to several cerebral conditions such as cerebral ischemia, brain trauma, and chronic neurodegenerative diseases [1,2,3,4,5]
We showed that mitochondrial dysfunction occurs during the reperfusion period following 2 h of focal cerebral ischemia in rats [12]
We examined the expression of the mitochondrial-specific proteins COX-I, which is encoded by mitochondrial deoxyribonucleic acid (mtDNA), and COX-IV, which is encoded by nuclear DNA
Summary
Essential roles of mitochondria include regulating energy metabolism, generating reactive oxygen species (ROS), and mediating apoptosis in response to several cerebral conditions such as cerebral ischemia, brain trauma, and chronic neurodegenerative diseases [1,2,3,4,5]. The mitochondrial mass increases and the aerobic set-point is maintained when neurons decline in function [5]. Several lines of evidence have shown that mitochondria are damaged during ischemic brain injury [6,7]. Evidence has shown that mitochondrial dysfunction aggravates neuronal injury after I-R because nerve cells are greatly dependent on mitochondria to support their high energy demand [11]. We showed that mitochondrial dysfunction occurs during the reperfusion period following 2 h of focal cerebral ischemia in rats [12]. Reperfusion after transient cerebral ischemia causes severe damage to mitochondria; 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
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