Chen Tingting, Majerníková Nad'a, Marmolejo-Garza Alejandro, Trombetta-Lima Marina, Sabogal-Guáqueta Angélica María, Zhang Yuequ, Ten Kate Ruth, Zuidema Minte, Mulder Patty P M F A, den Dunnen Wilfred, Gosens Reinoud, Verpoorte Elisabeth, Culmsee Carsten, Eisel Ulrich L M, Dolga Amalia M
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands; Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, the Netherlands.
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands; Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
Free Radic Biol Med. 2023 Nov 1;208:62-72. doi: 10.1016/j.freeradbiomed.2023.07.034. Epub 2023 Aug 1.
Ferroptosis is a type of oxidative cell death that can occur in neurodegenerative diseases and involves damage to mitochondria. Previous studies demonstrated that preventing mitochondrial dysfunction can rescue cells from ferroptotic cell death. However, the complexity of mitochondrial dysfunction and the timing of therapeutic interventions make it difficult to develop an effective treatment strategy against ferroptosis in neurodegeneration conditions. In this study, we explored the use of mitochondrial transplantation as a novel therapeutic approach for preventing ferroptotic neuronal cell death. Our data showed that isolated exogenous mitochondria were incorporated into both healthy and ferroptotic immortalized hippocampal HT-22 cells and primary cortical neurons (PCN). The mitochondrial incorporation was accompanied by increased metabolic activity and cell survival through attenuating lipid peroxidation and mitochondrial superoxide production. Further, the function of mitochondrial complexes I, III and V activities contributed to the neuroprotective activity of exogenous mitochondria. Similarly, we have also showed the internalization of exogenous mitochondria in mouse PCN; these internalized mitochondria were found to effectively preserve the neuronal networks when challenged with ferroptotic stimuli. The administration of exogenous mitochondria into the axonal compartment of a two-compartment microfluidic device induced mitochondrial transportation to the cell body, which prevented fragmentation of the neuronal network in ferroptotic PCN. These findings suggest that mitochondria transplantation may be a promising therapeutic approach for protecting neuronal cells from ferroptotic cell death.
铁死亡是一种可发生于神经退行性疾病的氧化性细胞死亡，且涉及线粒体损伤。先前的研究表明，预防线粒体功能障碍可使细胞免于铁死亡。然而，线粒体功能障碍的复杂性以及治疗干预的时机使得在神经退行性疾病条件下难以制定有效的抗铁死亡治疗策略。在本研究中，我们探索了将线粒体移植作为一种预防铁死亡神经元细胞死亡的新型治疗方法。我们的数据表明，分离的外源性线粒体可被健康的和发生铁死亡的永生化海马HT-22细胞以及原代皮质神经元（PCN）摄取。线粒体摄取伴随着代谢活性增加和细胞存活，这是通过减弱脂质过氧化和线粒体超氧化物生成实现的。此外，线粒体复合物I、III和V的活性功能有助于外源性线粒体的神经保护活性。同样，我们也证明了外源性线粒体在小鼠PCN中的内化；当受到铁死亡刺激时，这些内化的线粒体被发现能有效保护神经元网络。将外源性线粒体注入双室微流控装置的轴突区室可诱导线粒体向细胞体运输，这防止了发生铁死亡的PCN中神经元网络的碎片化。这些发现表明，线粒体移植可能是一种保护神经元细胞免于铁死亡的有前景的治疗方法。
