PINK1/Parkin-mediated mitophagy in mechanical ventilation-induced diaphragmatic dysfunction

作者全名："Yong, Hui; Zhou, Yun; Ye, Wanlin; Li, Tianmei; Wu, Gangming; Chen, Jingyuan; Liu, Li; Wei, Jicheng"

作者地址："[Yong, Hui; Zhou, Yun; Ye, Wanlin; Li, Tianmei; Liu, Li; Wei, Jicheng] Southwest Med Univ, Affiliated Hosp 1, Dept Anesthesiol, 25 Taiping St, Luzhou 646000, Sichuan, Peoples R China; [Wu, Gangming; Chen, Jingyuan] Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China"

通信作者："Liu, L (corresponding author), Southwest Med Univ, Affiliated Hosp 1, Dept Anesthesiol, 25 Taiping St, Luzhou 646000, Sichuan, Peoples R China."

来源：THERAPEUTIC ADVANCES IN RESPIRATORY DISEASE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000709233700001

JCR分区：Q2

影响因子：4.3

年份：2021

卷号：15

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：diaphragmatic dysfunction; mechanical ventilation; mitochondrial autophagy

摘要："Background: Mechanical ventilation (MV) often leads to ventilation-induced diaphragm dysfunction (VIDD). Although the development of this disorder had been linked to oxidative stress, mitochondrial energy deficiency, autophagy activation, and apoptosis in the diaphragm, it remains unclear whether the activation of mitophagy can induce VIDD. With our research, our endeavor is to uncover whether PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy affects the MV-caused diaphragmatic dysfunction Methods: Sprague-Dawley rats were subjected to MV treatment for 6 h (MV-6h), 12 h (MV-12h), or 24 h (MV-24h). Post MV, the diaphragm muscle compound action potential (CMAP) and cross-sectional areas (CSAs) of the diaphragm of these rats were measured. The levels of proteins of interest were examined to assess muscle health, mitochondrial dynamics, and mitophagy in the diaphragm. The co-localization of PINK1 with the mitochondrial protein marker tom20 was examined, as well as transmission electron microscopy analysis to detect changes in diaphragm mitochondrial ultrastructure. Results: MV-12h and MV-24h treatments resulted in a decrease in CSA of diaphragm and CMAP amplitude. In addition, the expressions of F-box (MFAbx), muscle-specific ring finger 1 (MURF1), PINK1, and p62 were elevated in rats treated with MV for 12 h and 24 h, while mfn2 expression was reduced. Rats following MV-24h treatment displayed an increase in mitochondrial dynamic protein (Drp1) and Parkin expression and microtubule-associated protein 1 light chain 3/1 (LC3II/I) ratio. Moreover, decreased SOD and GSH activity and membrane potential were observed after MV-12h and MV-24h treatment, while H2O2 activity increased after MV-24h treatment. In addition, a strong co-localization between PINK1 and tom20 was identified. Conclusion: These results reveal that MV leads to various changes in mitochondrial dynamics and significantly increases the mitophagy levels, which subsequently cause the variation in diaphragmatic function and muscle atrophy, indicating that mitophagy could be one of the possible mechanisms by which MV induces diaphragmatic dysfunction. The reviews of this paper are available via the supplemental material section."

基金机构：National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81772128]

基金资助正文："The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the National Natural Science Foundation of China (No. 81772128)."