Reversible Thiol Oxidation Increases Mitochondrial Electron Transport Complex Enzyme Activity but Not Respiration in Cardiomyocytes from Patients with End-Stage Heart Failure.
Reversible Thiol Oxidation Increases Mitochondrial Electron Transport Complex Enzyme Activity but Not Respiration in Cardiomyocytes from Patients with End-Stage Heart Failure.
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终末期心力衰竭伴射血分数降低（HFrEF）患者的心肌细胞功能障碍源于线粒体功能障碍，导致能量危机。据报道，线粒体功能障碍与氧化应激标志物的增加有关，但可逆性硫醇氧化对HFrEF患者心肌线粒体功能的影响尚未研究。在本研究中，我们评估了终末期HFrEF患者在存在和不存在硫醇还原剂二硫代苏糖醇（DTT）的情况下心室活检的线粒体功能。分离的线粒体暴露于DTT后，电子传递系统复合物I （p = 0.009）和III （p = 0.018）酶活性增加，复合物II （p = 0.630）和IV （p = 0.926）酶活性无变化。然而，增加的酶活性并没有延续到线粒体呼吸在渗透束的测量。氧化磷酸化电导（p = 0.439）、最大呼吸（p = 0.312）和ADP敏感性（p = 0.514）经5 mM DTT处理后无明显变化。这些结果表明，线粒体功能可以通过可逆的硫醇氧化来调节，但线粒体能量传递的其他成分在终末期HFrEF中是限速的。使终末期HFrEF患者心脏线粒体呼吸正常化的最佳疗法可能受益于逆转硫醇氧化的干预，这限制了复合物I和III的活性。
Cardiomyocyte dysfunction in patients with end-stage heart failure with reduced ejection fraction (HFrEF) stems from mitochondrial dysfunction, which contributes to an energetic crisis. Mitochondrial dysfunction reportedly relates to increased markers of oxidative stress, but the impact of reversible thiol oxidation on myocardial mitochondrial function in patients with HFrEF has not been investigated. In the present study, we assessed mitochondrial function in ventricular biopsies from patients with end-stage HFrEF in the presence and absence of the thiol-reducing agent dithiothreitol (DTT). Isolated mitochondria exposed to DTT had increased enzyme activity of complexes I (p = 0.009) and III (p = 0.018) of the electron transport system, while complexes II (p = 0.630) and IV (p = 0.926) showed no changes. However, increased enzyme activity did not carry over to measurements of mitochondrial respiration in permeabilized bundles. Oxidative phosphorylation conductance (p = 0.439), maximal respiration (p = 0.312), and ADP sensitivity (p = 0.514) were unchanged by 5 mM DTT treatment. These results indicate that mitochondrial function can be modulated through reversible thiol oxidation, but other components of mitochondrial energy transfer are rate limiting in end-stage HFrEF. Optimal therapies to normalize cardiac mitochondrial respiration in patients with end-stage HFrEF may benefit from interventions to reverse thiol oxidation, which limits complex I and III activities.
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DOI：
10.1016/s0735-1097(02)02600-1
发表时间：
2002-12-18
影响因子：
24
作者：
Scheubel, RJ;Tostlebe, M;Holtz, J
通讯作者：
Holtz, J
影响因子：
2.9
作者：
Glancy, Brian;Willis, Wayne T.;Balaban, Robert S.
通讯作者：
Balaban, Robert S.
影响因子：
9.7
作者：
Chaanine, Antoine H.;Joyce, Lyle D.;Redfield, Margaret M.
通讯作者：
Redfield, Margaret M.
影响因子：
4.8
作者：
Beer, SM;Taylor, ER;Murphy, MP
通讯作者：
Murphy, MP
影响因子：
8.8
作者：
Fisher-Wellman KH;Davidson MT;Narowski TM;Lin CT;Koves TR;Muoio DM
通讯作者：
Muoio DM