Aberrant mitochondrial dynamics contributes to diaphragmatic weakness induced by mechanical ventilation.
Aberrant mitochondrial dynamics contributes to diaphragmatic weakness induced by mechanical ventilation.
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DOI：
10.1093/pnasnexus/pgad336
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发表时间：
2023-11
期刊：
影响因子：
--
通讯作者：
Matecki, Stefan
中科院分区：
文献类型：
--
作者：
Dridi, Haikel;Yehya, Marc;Barsotti, Robert;Liu, Yang;Reiken, Steven;Azria, Lan;Yuan, Qi;Bahlouli, Laith;Soni, Rajesh Kumar;Marks, Andrew R.;Lacampagne, Alain;Matecki, Stefan
在重症监护患者中，机械通气（MV）引起的膈肌暂时不活动引发一系列事件，导致膈肌功能障碍和萎缩，通常称为呼吸机诱发的膈肌功能障碍（VIDD）。虽然与氧化应激相关的线粒体功能障碍被认为是VIDD的关键因素，但确切的分子机制仍然知之甚少。在这项研究中，我们观察到6小时的MV触发异常线粒体动力学，导致线粒体大小和相互作用减少，与动力蛋白相关蛋白1 （DRP1）的表达增加有关。这种效应可以通过P110来阻止，P110是一种抑制DRP1向线粒体膜募集的分子。此外，从通气患者膈膜分离的线粒体显示出活性氧（ROS）的增加。这些线粒体变化与1型ryanodine受体（RyR1）的快速氧化和稳定亚基calstabin 1的减少有关。随后，我们观察到通气膈肌浆网（SR）钙渗漏增加，收缩功能降低。重要的是，线粒体裂变抑制剂P110有效地阻止了所有这些改变。综上所述，我们的研究结果表明，横膈膜中的MV导致线粒体断裂和功能障碍，与320种蛋白质的上调/下调有关，通过全球全面定量蛋白质组学分析评估，主要与线粒体功能相关。这些结果强调了开发旨在调节线粒体裂变和融合之间平衡的化合物作为减轻人类患者VIDD的潜在干预措施的重要性。
In critical care patients, the “”temporary inactivity of the diaphragm caused by mechanical ventilation (MV) triggers a series of events leading to diaphragmatic dysfunction and atrophy, commonly known as ventilator-induced diaphragm dysfunction (VIDD). While mitochondrial dysfunction related to oxidative stress is recognized as a crucial factor in VIDD, the exact molecular mechanism remains poorly understood. In this study, we observe that 6 h of MV triggers aberrant mitochondrial dynamics, resulting in a reduction in mitochondrial size and interaction, associated with increased expression of dynamin-related protein 1 (DRP1). This effect can be prevented by P110, a molecule that inhibits the recruitment of DRP1 to the mitochondrial membrane. Furthermore, isolated mitochondria from the diaphragms of ventilated patients exhibited increased production of reactive oxygen species (ROS). These mitochondrial changes were associated with the rapid oxidation of type 1 ryanodine receptor (RyR1) and a decrease in the stabilizing subunit calstabin 1. Subsequently, we observed that the sarcoplasmic reticulum (SR) in the ventilated diaphragms showed increased calcium leakage and reduced contractile function. Importantly, the mitochondrial fission inhibitor P110 effectively prevented all of these alterations. Taken together, the results of our study illustrate that MV leads, in the diaphragm, to both mitochondrial fragmentation and dysfunction, linked to the up-/down-regulation of 320 proteins, as assessed through global comprehensive quantitative proteomics analysis, primarily associated with mitochondrial function. These outcomes underscore the significance of developing compounds aimed at modulating the balance between mitochondrial fission and fusion as potential interventions to mitigate VIDD in human patients.
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影响因子：
11.1
作者：
Joshi AU;Saw NL;Vogel H;Cunnigham AD;Shamloo M;Mochly-Rosen D
通讯作者：
Mochly-Rosen D
影响因子：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
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