Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury
Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury
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DOI：
10.1523/jneurosci.3415-17.2018
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发表时间：
2019-03-06
影响因子：
5.3
通讯作者：
Ji, Jing
中科院分区：
文献类型：
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作者：
Chao, Honglu;Lin, Chao;Ji, Jing
线粒体能量的产生对正常的大脑功能至关重要。创伤性脑损伤（TBI）增加了大脑的能量需求，导致线粒体呼吸的激活，与活性氧的产生增加有关。这一系列事件通过线粒体特异性磷脂——心磷脂（CL）的氧化触发神经元凋亡。细胞避免凋亡的一个途径是通过线粒体自噬消除受损的线粒体。先前，我们发现CL外化到线粒体表面在细胞中作为一种消除信号。cl介导的线粒体自噬是否在体内发生或其在疾病过程中的意义尚不清楚。在这项研究中，我们发现TBI导致人脑中线粒体自噬增加，在雄性大鼠的TBI模型中也检测到了这一点。负责CL从头合成的CL合成酶或负责CL向线粒体外膜易位的磷脂转录酶-3的敲低可显著降低tbi诱导的线粒体自噬。TBI后3-甲基腺嘌呤、mdivi-1或磷脂转录酶-3敲低对线粒体清除的抑制导致更差的结果，这表明线粒体自噬是有益的。总之，我们的研究结果表明，tbi诱导的线粒体自噬是一种内源性的神经保护过程，由CL指导，它标记受损的线粒体以消除，从而限制神经元死亡和行为缺陷。
Mitochondrial energy production is essential for normal brain function. Traumatic brain injury (TBI) increases brain energy demands, results in the activation of mitochondrial respiration, associated with enhanced generation of reactive oxygen species. This chain of events triggers neuronal apoptosis via oxidation of a mitochondria-specific phospholipid, cardiolipin (CL). One pathway through which cells can avoid apoptosis is via elimination of damaged mitochondria by mitophagy. Previously, we showed that externalization of CL to the mitochondrial surface acts as an elimination signal in cells. Whether CL-mediated mitophagy occurs in vivo or its significance in the disease processes are not known. In this study, we showed that TBI leads to increased mitophagy in the human brain, which was also detected using TBI models in male rats. Knockdown of CL synthase, responsible for de novo synthesis of CL, or phospholipid scramblase-3, responsible for CL translocat ion to the outer mitochondrial membrane, significantly decreased TBI-induced mitophagy. Inhibition of mitochondrial clearance by 3-methyladenine, mdivi-1, or phospholipid scramblase-3 knockdown after TBI led to a worse outcome, suggesting that mitophagy is beneficial. Together, our findings indicate that TBI-induced mitophagy is an endogenous neuroprotective process that is directed by CL, which marks damaged mitochondria for elimination, thereby limiting neuronal death and behavioral deficits.