Butyrate Feeding Reverses CypD-Related Mitoflash Phenotypes in Mouse Myofibers.
Butyrate Feeding Reverses CypD-Related Mitoflash Phenotypes in Mouse Myofibers.
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丁酸酯喂养逆转小鼠肌纤维中与CYPD相关的丝线相关表型。
DOI：
10.3390/ijms22147412
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发表时间：
2021-07-10
影响因子：
5.6
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Li A;Li X;Yi J;Ma J;Zhou J
线粒体闪光是生物传感器mt-cpYFP的自发瞬变。在心肌细胞中，线粒体闪光与亲环素D（CypD）介导的线粒体通透性转换孔（mPTP）的开放相关，而在骨骼肌中，它们被认为是生理条件下线粒体呼吸爆发的标志。在这里，我们评估了mitoflashs和mPTP开放在不同CypD水平和磷酸化状态之间的潜在关联，通过产生三个CypD衍生的融合构建体与红移，pH稳定的Ca 2+传感器jRCaMP 1b。我们观察到在CypD和CypDS 42 A（丝氨酸42处的磷酸盐抗性突变）过表达的肌纤维中伴随线粒体闪光的核周线粒体Ca 2+流出，但在表达CypD（CypDN 30）的靶向序列的对照肌纤维中没有观察到。通过一个新开发的分析程序的帮助下，我们确定了更短，更频繁的mitoflash活动发生在更大的面积CypD和CypDS 42 A过表达的肌纤维比对照CypDN 30肌纤维。这些观察结果提供了先前观察到的肌萎缩侧索硬化症（ALS）小鼠模型中后肢肌肉中CypD表达升高和线粒体闪光活性增加之间的关联。更重要的是，用丁酸钠喂养小鼠逆转了CypD相关的mitoflash表型，并防止CypD的异位上调，揭示了丁酸盐介导的缓解小鼠模型ALS进展的新分子机制。
Mitoflashes are spontaneous transients of the biosensor mt-cpYFP. In cardiomyocytes, mitoflashes are associated with the cyclophilin D (CypD) mediated opening of mitochondrial permeability transition pore (mPTP), while in skeletal muscle they are considered hallmarks of mitochondrial respiration burst under physiological conditions. Here, we evaluated the potential association between mitoflashes and the mPTP opening at different CypD levels and phosphorylation status by generating three CypD derived fusion constructs with a red shifted, pH stable Ca2+ sensor jRCaMP1b. We observed perinuclear mitochondrial Ca2+ efflux accompanying mitoflashes in CypD and CypDS42A (a phosphor-resistant mutation at Serine 42) overexpressed myofibers but not the control myofibers expressing the mitochondria-targeting sequence of CypD (CypDN30). Assisted by a newly developed analysis program, we identified shorter, more frequent mitoflash activities occurring over larger areas in CypD and CypDS42A overexpressed myofibers than the control CypDN30 myofibers. These observations provide an association between the elevated CypD expression and increased mitoflash activities in hindlimb muscles in an amyotrophic lateral sclerosis (ALS) mouse model previously observed. More importantly, feeding the mice with sodium butyrate reversed the CypD-associated mitoflash phenotypes and protected against ectopic upregulation of CypD, unveiling a novel molecular mechanism underlying butyrate mediated alleviation of ALS progression in the mouse model.
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影响因子：
64.5
作者：
Ichas, F;Jouaville, LS;Mazat, JP
通讯作者：
Mazat, JP
影响因子：
29
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Donohoe DR;Garge N;Zhang X;Sun W;O'Connell TM;Bunger MK;Bultman SJ
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Bultman SJ
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4.8
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Cheng, Heping
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作者：
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通讯作者：
Balaban, Robert S.
影响因子：
4.1
作者：
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