Membrane potential-dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue.
Membrane potential-dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue.
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草乙酸酯在刺激棕色脂肪组织中对线粒体复合物II对线粒体复合物II的调节。
DOI：
10.1096/fba.2021-00137
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发表时间：
2022-03
影响因子：
2.7
通讯作者：
Sivitz WI
中科院分区：
文献类型：
--
作者：
Fink BD;Rauckhorst AJ;Taylor EB;Yu L;Sivitz WI
通常，线粒体呼吸通过增加呼吸来响应膜电位的降低（ΔΨ）。然而，我们发现，对于骨骼肌线粒体中琥珀酸激活的复合物II呼吸（不受鱼藤酮的阻碍），低ΔΨ通过草酰乙酸（OAA）抑制琥珀酸脱氢酶（SDH）的机制损害呼吸。在这里，我们研究了这种现象是否延伸到一个组织的不同线粒体，其中ΔΨ本质上是低的，即肩胛间棕色脂肪组织（IBAT）。此外，为了提高我们对机制的认识，我们进行了代谢物通量的同位素研究，这在我们以前的肌肉研究中没有做过。在其他新的工作中，我们探讨了ADP可能影响IBAT线粒体机制的可能途径。UCP1活性和ΔΨ同时受到GDP（一种公认的UCP1有效抑制剂）和化学解偶联剂羰基氰化物-间氯苯腙（FCCP）的干扰。在琥珀酸激活的线粒体中，GDP增加ΔΨ，但也增加而不是减少（正如在低ΔΨ下的经典预测）O2通量。在GDP处理的线粒体中，FCCP降低了电位，但也降低了呼吸。NMR代谢物研究和LC - MS通量分析支持了一种机制，其中ΔΨ对活性氧产生的影响改变了影响OAA积累的NADH/NAD+比例，从而影响了OAA对SDH的抑制。我们还发现，ADP以复杂的方式改变复合体II呼吸可能涉及由于ATP合成，GDP样核苷酸抑制UCP1和变构酶作用而减少ΔΨ。综上所述，IBAT线粒体中的复合体II呼吸受UCP1依赖性ΔΨ调节，通过OAA和OAA抑制SDH改变底物流动。
Classically, mitochondrial respiration responds to decreased membrane potential (ΔΨ) by increasing respiration. However, we found that for succinate‐energized complex II respiration in skeletal muscle mitochondria (unencumbered by rotenone), low ΔΨ impairs respiration by a mechanism culminating in oxaloacetate (OAA) inhibition of succinate dehydrogenase (SDH). Here, we investigated whether this phenomenon extends to far different mitochondria of a tissue wherein ΔΨ is intrinsically low, i.e., interscapular brown adipose tissue (IBAT). Also, to advance our knowledge of the mechanism, we performed isotopomer studies of metabolite flux not done in our previous muscle studies. In additional novel work, we addressed possible ways ADP might affect the mechanism in IBAT mitochondria. UCP1 activity, and consequently ΔΨ, were perturbed both by GDP, a well‐recognized potent inhibitor of UCP1 and by the chemical uncoupler carbonyl cyanide m‐chlorophenyl hydrazone (FCCP). In succinate‐energized mitochondria, GDP increased ΔΨ but also increased rather than decreased (as classically predicted under low ΔΨ) O2 flux. In GDP‐treated mitochondria, FCCP reduced potential but also decreased respiration. Metabolite studies by NMR and flux analyses by LC‐MS support a mechanism, wherein ΔΨ effects on the production of reactive oxygen alters the NADH/NAD+ ratio affecting OAA accumulation and, hence, OAA inhibition of SDH. We also found that ADP‐altered complex II respiration in complex fashion probably involving decreased ΔΨ due to ATP synthesis, a GDP‐like nucleotide inhibition of UCP1, and allosteric enzyme action. In summary, complex II respiration in IBAT mitochondria is regulated by UCP1‐dependent ΔΨ altering substrate flow through OAA and OAA inhibition of SDH.
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影响因子：
7.3
作者：
Ma, Tianfan;Zou, Fangxia;Zha, Xiaoming
通讯作者：
Zha, Xiaoming
影响因子：
2.6
作者：
Al Kadhi O;Melchini A;Mithen R;Saha S
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Chouchani, Edward T.;Pell, Victoria R.;Gaude, Edoardo;Aksentijevic, Dunja;Sundier, Stephanie Y.;Robb, Ellen L.;Logan, Angela;Nadtochiy, Sergiy M.;Ord, Emily N. J.;Smith, Anthony C.;Eyassu, Filmon;Shirley, Rachel;Hu, Chou-Hui;Dare, Anna J.;James, Andrew M.;Rogatti, Sebastian;Hartley, Richard C.;Eaton, Simon;Costa, Ana S. H.;Brookes, Paul S.;Davidson, Sean M.;Duchen, Michael R.;Saeb-Parsy, Kourosh;Shattock, Michael J.;Robinson, Alan J.;Work, Lorraine M.;Frezza, Christian;Krieg, Thomas;Murphy, Michael P.
通讯作者：
Murphy, Michael P.
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
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BAX, A
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64.8
作者：
AZZONE, GF;ERNSTER, L;KLINGENBERG, M
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KLINGENBERG, M