Feng Yansheng, Imam Aliagan Abdulhafiz, Tombo Nathalie, Bopassa Jean C
Department of Cellular and Integrative Physiology, School of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA.
Antioxidants (Basel). 2023 Apr 13;12(4):921. doi: 10.3390/antiox12040921.
Mitochondrial inner membrane protein (Mitofilin/Mic60) is part of a big complex that constituent the mitochondrial inner membrane organizing system (MINOS), which plays a critical role in maintaining mitochondrial architecture and function. We recently showed that Mitofilin physically binds to Cyclophilin D, and disruption of this interaction promotes the opening of mitochondrial permeability transition pore (mPTP) and determines the extent of I/R injury. Here, we investigated whether Mitofilin knockout in the mouse enhances myocardial injury and inflammation after I/R injury. We found that full-body deletion (homozygote) of Mitofilin induces a lethal effect in the offspring and that a single allele expression of Mitofilin is sufficient to rescue the mouse phenotype in normal conditions. Using non-ischemic hearts from wild-type (WT) and Mitofilin (HET) mice, we report that the mitochondria structure and calcium retention capacity (CRC) required to induce the opening of mPTP were similar in both groups. However, the levels of mitochondrial dynamics proteins involved in both fusion/fission, including MFN2, DRP1, and OPA1, were slightly reduced in Mitofilin mice compared to WT. After I/R, the CRC and cardiac functional recovery were reduced while the mitochondria structure was more damaged, and myocardial infarct size was increased in Mitofilin mice compared to WT. Mitofilin mice exhibited an increase in the mtDNA release in the cytosol and ROS production, as well as dysregulated SLC25As (3, 5, 11, and 22) solute carrier function, compared to WT. In addition, Mitofilin mice displayed an increase in the transcript of pro-inflammatory markers, including IL-6, ICAM, and TNF-α. These results suggest that Mitofilin knockdown induces mitochondrial cristae damage that promotes dysregulation of SLC25As solute carriers, leading to an increase in ROS production and reduction in CRC after I/R. These effects are associated with an increase in the mtDNA release into the cytosol, where it activates signaling cascades leading to nuclear transcription of pro-inflammatory cytokines that aggravate I/R injury.
线粒体内膜蛋白（Mitofilin/Mic60）是构成线粒体内膜组织系统（MINOS）的一个大型复合体的一部分，该系统在维持线粒体结构和功能方面起着关键作用。我们最近发现Mitofilin与亲环蛋白D发生物理结合，这种相互作用的破坏会促进线粒体通透性转换孔（mPTP）的开放，并决定缺血/再灌注（I/R）损伤的程度。在此，我们研究了小鼠中Mitofilin基因敲除是否会加重I/R损伤后的心肌损伤和炎症反应。我们发现Mitofilin的全身缺失（纯合子）会在子代中诱导致死效应，而Mitofilin的单等位基因表达足以在正常条件下挽救小鼠表型。利用野生型（WT）和Mitofilin（HET）小鼠的非缺血心脏，我们报告两组中诱导mPTP开放所需的线粒体结构和钙保留能力（CRC）相似。然而，与WT相比，Mitofilin小鼠中参与融合/裂变的线粒体动力学蛋白水平略有降低，包括MFN2、DRP1和OPA1。I/R后，与WT相比，Mitofilin小鼠的CRC和心脏功能恢复降低，而线粒体结构受损更严重，心肌梗死面积增加。与WT相比，Mitofilin小鼠的胞质中线粒体DNA释放增加、活性氧生成增加，以及溶质载体功能失调的溶质载体家族25成员A（SLC25As，3、5、11和22）。此外，Mitofilin小鼠中促炎标志物的转录本增加，包括白细胞介素-6（IL-6）、细胞间黏附分子（ICAM）和肿瘤坏死因子-α（TNF-α）。这些结果表明，Mitofilin敲低会诱导线粒体嵴损伤，从而促进溶质载体家族25成员A溶质载体的失调，导致I/R后活性氧生成增加和CRC降低。这些效应与线粒体DNA释放到胞质中增加有关，在胞质中它激活信号级联反应，导致促炎细胞因子的核转录，从而加重I/R损伤。
