Sex differences in mitochondrial biogenesis determine neuronal death and survival in response to oxygen glucose deprivation and reoxygenation.
Sex differences in mitochondrial biogenesis determine neuronal death and survival in response to oxygen glucose deprivation and reoxygenation.
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DOI：
10.1186/1471-2202-15-9
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发表时间：
2014-01-10
期刊：
影响因子：
2.4
通讯作者：
Hossain MA
中科院分区：
文献类型：
--
作者：
Sharma J;Johnston MV;Hossain MA
线粒体功能障碍与神经元死亡和一系列神经退行性疾病有关。之前，我们已经证明了缺氧缺血后线粒体介导的细胞死亡途径的性别差异。然而，线粒体生物发生在男女缺氧缺血性脑损伤中的作用尚未得到研究。从P7雄性小鼠（CD-1）和雌性小鼠（CD-1）中分离出初级小脑颗粒神经元（CGNs），进行2小时的氧葡萄糖剥夺（OGD）和6-24小时的再氧化（Reox）。与XY CGNs相比，XX CGNs的线粒体膜电位（ΔΨm）和细胞ATP水平显著降低。与XX神经元和正常缺氧对照相比，XY CGNs线粒体DNA （mtDNA）含量在OGD 2 h时增加了约2倍，并且在Reox 24 h时仍保持增加。线粒体转录因子A （Tfam）、核呼吸因子-1 （NRF-1）和线粒体生物发生的主要调控因子过氧化物酶体增殖因子激活受体γ共激活因子-1α (PGC-1α)的表达在XY CGNs中上调（2倍，***p < 0.001），而在XX神经元中略有降低或保持不变。同样，仅在XY神经元中，TFAM和PGC-1α蛋白水平以及线粒体蛋白HSP60和COXIV水平升高。与XX神经元相比，XY CGNs对融合（Mfn 1和Mfn 2）和裂变（Fis 1和Drp 1）基因的刺激平衡，并增强了甜甜圈状线粒体的形成（**p < 0.01）。我们的研究结果表明，OGD/Reox以性别特异性的方式改变线粒体的生物发生和形态变化，对两性神经元损伤/存活的影响不同。
Mitochondrial dysfunction has been linked to neuronal death and a wide array of neurodegenerative diseases. Previously, we have shown sex differences in mitochondria-mediated cell death pathways following hypoxia-ischemia. However, the role of mitochondrial biogenesis in hypoxic-ischemic brain injury between male vs. female has not been studied yet. Primary cerebellar granule neurons (CGNs), isolated from P7 male and female mice (CD-1) segregated based on visual inspection of sex, were exposed to 2 h of oxygen glucose deprivation (OGD) followed by 6–24 h of reoxygenation (Reox). Mitochondrial membrane potential (ΔΨm) and cellular ATP levels were reduced significantly in XX CGNs as compared to XY CGNs. Mitochondrial DNA (mtDNA) content was increased (>2-fold) at 2 h OGD in XY CGNs and remained increased up to 24 h of Reox compared to XX neurons and normoxia controls. The expression of mitochondrial transcription factor A (Tfam), the nuclear respiratory factor-1 (NRF-1) and the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, were up-regulated (2-fold, ***p < 0.001) in XY CGNs but slightly reduced or remained unchanged in XX neurons. Similarly, the TFAM and PGC-1α protein levels and the mitochondrial proteins HSP60 and COXIV were increased in XY neurons only. Supportively, a balanced stimulation of fusion (Mfn 1and Mfn 2) and fission (Fis 1 and Drp 1) genes and enhanced formation of donut-shaped mitochondria were observed in XY CGNs vs. XX neurons (**p < 0.01). Our results demonstrate that OGD/Reox alters mitochondrial biogenesis and morphological changes in a sex-specific way, influencing neuronal injury/survival differently in both sexes.
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DOI：
10.1083/jcb.200306132
发表时间：
2003-11-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kaufman BA;Kolesar JE;Perlman PS;Butow RA
通讯作者：
Butow RA
影响因子：
12.4
作者：
通讯作者：
--
DOI：
10.1196/annals.1378.003
发表时间：
2006-01-01
期刊：
SIGNAL TRANSDUCTION PATHWAYS, PT A
影响因子：
--
作者：
Bertoni-Freddari, Carlo;Fattoretti, Patrizia;De Angelis, Clara
通讯作者：
De Angelis, Clara
DOI：
10.1083/jcb.200211046
发表时间：
2003-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
通讯作者：
Chan DC
影响因子：
1.9
作者：
Golomb, Meredith R.;Garg, Bhuwan P.;Williams, Linda S.
通讯作者：
Williams, Linda S.