Departments of Neurosurgery and.
Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health.
J Neurosci. 2019 Mar 6;39(10):1930-1943. doi: 10.1523/JNEUROSCI.3415-17.2018. Epub 2019 Jan 9.
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 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 synthesis of CL, or phospholipid scramblase-3, responsible for CL translocation 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. Traumatic brain injury (TBI) increases energy demands leading to activation of mitochondrial respiration associated with enhanced generation of reactive oxygen species and resultant damage to mitochondria. We demonstrate that the complete elimination of irreparably damaged organelles via mitophagy is activated as an early response to TBI. This response includes translocation of mitochondria phospholipid cardiolipin from the inner membrane to the outer membrane where externalized cardiolipin mediates targeted protein light chain 3-mediated autophagy of damaged mitochondria. Our data on targeting phospholipid scramblase and cardiolipin synthase in genetically manipulated cells and animals strongly support the essential role of cardiolipin externalization mechanisms in the endogenous reparative plasticity of injured brain cells. Furthermore, successful execution and completion of mitophagy is beneficial in the context of preservation of cognitive functions after TBI.
线粒体能量产生对于正常的大脑功能至关重要。创伤性脑损伤 (TBI) 会增加大脑的能量需求，导致线粒体呼吸的激活，伴随着活性氧的产生增加。这一连串事件通过氧化一种线粒体特异性磷脂，心磷脂 (CL)，触发神经元凋亡。细胞可以避免凋亡的一种途径是通过自噬作用消除受损的线粒体。先前，我们表明 CL 向线粒体表面的外排在细胞中作为一种消除信号。CL 介导的自噬是否发生及其在疾病过程中的意义尚不清楚。在这项研究中，我们表明 TBI 导致人脑中的自噬增加，这在雄性大鼠的 TBI 模型中也被检测到。CL 合酶的敲低，负责 CL 的合成，或磷脂翻转酶-3，负责 CL 向线粒体外膜的易位，显著降低了 TBI 诱导的自噬。TBI 后用 3-甲基腺嘌呤、mdivi-1 或磷脂翻转酶-3 敲低抑制线粒体清除会导致更糟糕的结果，表明自噬是有益的。总之，我们的研究结果表明，TBI 诱导的自噬是一种内源性神经保护过程，由 CL 指导，CL 标记受损的线粒体进行清除，从而限制神经元死亡和行为缺陷。创伤性脑损伤 (TBI) 增加能量需求，导致线粒体呼吸的激活与活性氧的产生增加以及线粒体的损伤有关。我们证明，通过自噬完全消除不可修复的细胞器是作为 TBI 的早期反应而被激活的。这种反应包括线粒体磷脂心磷脂从内膜向外膜的易位，在外膜上心磷脂介导靶向蛋白轻链 3 介导的受损线粒体的自噬。我们在基因操纵细胞和动物中的靶向磷脂翻转酶和心磷脂合酶的数据强烈支持心磷脂外排机制在心脑细胞内源性修复可塑性中的重要作用。此外，在 TBI 后认知功能的保存方面，成功执行和完成自噬是有益的。
