Chronic Hypoxia Inhibits Respiratory Complex IV Activity and Disrupts Mitochondrial Dynamics in the Fetal Guinea Pig Forebrain.
Chronic Hypoxia Inhibits Respiratory Complex IV Activity and Disrupts Mitochondrial Dynamics in the Fetal Guinea Pig Forebrain.
复制标题
慢性缺氧抑制呼吸复合物 IV 活性并扰乱胎儿豚鼠前脑的线粒体动态。
DOI：
10.1007/s43032-021-00779-w
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Thompson,LorenP
中科院分区：
文献类型：
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作者：
Quebedeaux,TabithaM;Song,Hong;Giwa-Otusajo,Jamiu;Thompson,LorenP
线粒体功能障碍是儿童神经系统疾病的根本原因，继发于线粒体在正常神经发育中的关键作用。我们推测，慢性宫内缺氧（HPX）诱导线粒体缺陷，通过改变线粒体生物合成和动力学在胎儿大脑。妊娠豚鼠从妊娠28天（早发性，EO-HPX）或50天（晚发性，LO-HPX）开始暴露于常氧（NMX，21%O2）或HPX（10.5%O2），直至足月（65天）。从麻醉母猪中提取近期雄性和雌性胎仔，并从切除的胎仔前脑中分离线粒体（n= 6/组）。通过Western印迹法测定线粒体复合物亚基I-V（CI-CV）、分裂（Drp-1）和融合（Mfn-2）蛋白的表达。通过比色测定法测量CI和CIV酶活性。慢性HPX降低胎儿体重和增加（P< 0.05）脑/体重比的性别。与NMX相比，CV亚基水平仅在EO-HPX雄性动物中升高，CII水平仅在LO-HPX雌性动物中升高。EO-和LO-HPX降低两种性别的CIV活性，但对CI活性没有影响。EO-HPX增加了雄性动物的Drp 1水平，降低了Mfn 2水平，而LO-HPX对这两种蛋白水平均无影响。在雌性动物中，EO-HPX和LO-HPX均增加Drp 1，但对Mfn 2水平无影响。慢性HPX改变选择复杂亚基的丰度和活性，并在胎豚鼠脑中以性别依赖的方式将线粒体动力学向裂变方向转变。这可能是呼吸效率降低的潜在机制，导致代谢中断，并增加了HPX胎儿大脑出生时第二次神经损伤的脆弱性。
Mitochondrial dysfunction is an underlying cause of childhood neurological disease secondary to the crucial role of mitochondria in proper neurodevelopment. We hypothesized that chronic intrauterine hypoxia (HPX) induces mitochondrial deficits by altering mitochondrial biogenesis and dynamics in the fetal brain. Pregnant guinea pigs were exposed to either normoxia (NMX, 21%O2) or HPX (10.5%O2) starting at 28-day (early onset, EO-HPX) or 50-day (late onset, LO-HPX) gestation until term (65 days). Near-term male and female fetuses were extracted from anesthetized sows, and mitochondria were isolated from excised fetal forebrains (n= 6/group). Expression of mitochondrial complex subunits I–V (CI–CV), fission (Drp-1), and fusion (Mfn-2) proteins was measured by Western blot. CI and CIV enzyme activities were measured by colorimetric assays. Chronic HPX reduced fetal body wts and increased (P< 0.05) brain/body wt ratios of both sexes. CV subunit levels were increased in EO-HPX males only and CII levels increased in LO-HPX females only compared to NMX. Both EO- and LO-HPX decreased CIV activity in both sexes but had no effect on CI activity. EO-HPX increased Drp1 and decreased Mfn2 levels in males, while LO-HPX had no effect on either protein levels. In females, both EO-HPX and LO-HPX increased Drp1 but had no effect on Mfn2 levels. Chronic HPX alters abundance and activity of select complex subunits and shifts mitochondrial dynamics toward fission in a sex-dependent manner in the fetal guinea pig brain. This may be an underlying mechanism of reduced respiratory efficiency leading to disrupted metabolism and increased vulnerability to a second neurological injury at the time of birth in HPX fetal brains.