DJ-1 attenuates the glycation of mitochondrial complex I and complex III in the post-ischemic heart.
DJ-1 attenuates the glycation of mitochondrial complex I and complex III in the post-ischemic heart.
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DOI：
10.1038/s41598-021-98722-1
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发表时间：
2021-09-30
影响因子：
4.6
通讯作者：
Calvert JW
中科院分区：
文献类型：
--
作者：
Pantner Y;Polavarapu R;Chin LS;Li L;Shimizu Y;Calvert JW
DJ-1是一种普遍表达的蛋白质，通过将其转化为活性蛋白酶来保护细胞免受压力。最近的工作发现，DJ-1的活性形式在缺血心脏中被诱导，作为一种内源性机制，以减轻糖化应激--蛋白质的非酶糖基化。然而，DJ-1保护特定蛋白免受糖化应激的作用尚不清楚。鉴于线粒体电子传递蛋白有糖化应激的倾向，我们研究了DJ-1在心肌缺血再灌注损伤后是否调节复合体I和复合体III的糖基化。初步研究发现，DJ-1定位于线粒体，并在心肌I/R损伤后3天增加其与复合体I和复合体III的相互作用。接下来，我们研究了DJ-1在调节线粒体糖化应激中所起的作用。分析表明，与野生型对照小鼠相比，DJ-1缺陷型(DJ-1 KO)小鼠心脏线粒体在I/R后糖化应激水平增加。此外，DJ-1 KO心脏中发现复杂I和复杂III糖基化水平更高。这与丙酮酸和苹果酸存在时复合体活性降低以及线粒体耗氧量和ATP合成减少相对应。为了进一步确定DJ-1是否影响了复合体的糖基化，我们使用腺病毒方法过表达了DJ-1的活性形式(AAV9-DJ1ΔC)。在I/R条件下，AAV9-DJ1ΔC处理的心脏中，复合体I和复合体III的糖基化作用减弱，伴随着复合体活性、氧耗和三磷酸腺苷产生的改善。综上所述，这些数据表明，在I/R损伤的恢复过程中，心脏DJ-1保持着复合I和复合III的效率和线粒体功能。在阐明DJ-1‘S在缺血后心脏中作用的具体机制方面，这些数据为以DJ-1为靶点的潜在治疗策略开辟了新的基础。
DJ-1 is a ubiquitously expressed protein that protects cells from stress through its conversion into an active protease. Recent work found that the active form of DJ-1 was induced in the ischemic heart as an endogenous mechanism to attenuate glycative stress—the non-enzymatic glycosylation of proteins. However, specific proteins protected from glycative stress by DJ-1 are not known. Given that mitochondrial electron transport proteins have a propensity for being targets of glycative stress, we investigated if DJ-1 regulates the glycation of Complex I and Complex III after myocardial ischemia–reperfusion (I/R) injury. Initial studies found that DJ-1 localized to the mitochondria and increased its interaction with Complex I and Complex III 3 days after the onset of myocardial I/R injury. Next, we investigated the role DJ-1 plays in modulating glycative stress in the mitochondria. Analysis revealed that compared to wild-type control mice, mitochondria from DJ-1 deficient (DJ-1 KO) hearts showed increased levels of glycative stress following I/R. Additionally, Complex I and Complex III glycation were found to be at higher levels in DJ-1 KO hearts. This corresponded with reduced complex activities, as well as reduced mitochondrial oxygen consumption ant ATP synthesis in the presence of pyruvate and malate. To further determine if DJ-1 influenced the glycation of the complexes, an adenoviral approach was used to over-express the active form of DJ-1(AAV9-DJ1ΔC). Under I/R conditions, the glycation of Complex I and Complex III were attenuated in hearts treated with AAV9-DJ1ΔC. This was accompanied by improvements in complex activities, oxygen consumption, and ATP production. Together, this data suggests that cardiac DJ-1 maintains Complex I and Complex III efficiency and mitochondrial function during the recovery from I/R injury. In elucidating a specific mechanism for DJ-1’s role in the post-ischemic heart, these data break new ground for potential therapeutic strategies using DJ-1 as a target.
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影响因子：
4.2
作者：
de Arriba, Susana Garcia;Stuchbury, Grant;Muench, Gerald
通讯作者：
Muench, Gerald
影响因子：
3.4
作者：
Li, Yuan;Chang, Ye;Sun, Yingxian
通讯作者：
Sun, Yingxian
影响因子：
3.5
作者：
Lee, Ju-young;Song, Jeeyeon;Park, Chankyu
通讯作者：
Park, Chankyu
影响因子：
4.8
作者：
Brouwers, Olaf;Niessen, Petra M.;Schalkwijk, Casper G.
通讯作者：
Schalkwijk, Casper G.
DOI：
10.1016/j.bbrc.2016.03.056
发表时间：
2016-04-22
影响因子：
3.1
作者：
Advedissian, Tamara;Deshayes, Frederique;Richarme, Gilbert
通讯作者：
Richarme, Gilbert