Department of Anatomy and Neurobiology, University of Kentucky, 800 Rose Street, Lexington, KY 40536, USA.
Apoptosis. 2010 Nov;15(11):1336-53. doi: 10.1007/s10495-010-0465-0.
The structure and function of the mitochondrial network is regulated by mitochondrial biogenesis, fission, fusion, transport and degradation. A well-maintained balance of these processes (mitochondrial dynamics) is essential for neuronal signaling, plasticity and transmitter release. Core proteins of the mitochondrial dynamics machinery play important roles in the regulation of apoptosis, and mutations or abnormal expression of these factors are associated with inherited and age-dependent neurodegenerative disorders. In Parkinson's disease (PD), oxidative stress and mitochondrial dysfunction underlie the development of neuropathology. The recessive Parkinsonism-linked genes PTEN-induced kinase 1 (PINK1) and Parkin maintain mitochondrial integrity by regulating diverse aspects of mitochondrial function, including membrane potential, calcium homeostasis, cristae structure, respiratory activity, and mtDNA integrity. In addition, Parkin is crucial for autophagy-dependent clearance of dysfunctional mitochondria. In the absence of PINK1 or Parkin, cells often develop fragmented mitochondria. Whereas excessive fission may cause apoptosis, coordinated induction of fission and autophagy is believed to facilitate the removal of damaged mitochondria through mitophagy, and has been observed in some types of cells. Compensatory mechanisms may also occur in mice lacking PINK1 that, in contrast to cells and Drosophila, have only mild mitochondrial dysfunction and lack dopaminergic neuron loss. A better understanding of the relationship between the specific changes in mitochondrial dynamics/turnover and cell death will be instrumental to identify potentially neuroprotective pathways steering PINK1-deficient cells towards survival. Such pathways may be manipulated in the future by specific drugs to treat PD and perhaps other neurodegenerative disorders characterized by abnormal mitochondrial function and dynamics.
线粒体网络的结构和功能受线粒体生物发生、裂变、融合、运输和降解的调节。这些过程(线粒体动力学)的良好平衡对于神经元信号、可塑性和递质释放至关重要。线粒体动力学机制的核心蛋白在细胞凋亡的调节中起着重要作用,这些因素的突变或异常表达与遗传性和年龄相关性神经退行性疾病有关。在帕金森病(PD)中,氧化应激和线粒体功能障碍是神经病理学发展的基础。隐性帕金森病相关基因 PTEN 诱导激酶 1(PINK1)和 Parkin 通过调节线粒体功能的多个方面来维持线粒体的完整性,包括膜电位、钙稳态、嵴结构、呼吸活性和 mtDNA 完整性。此外,Parkin 对依赖自噬的功能失调线粒体的清除至关重要。在没有 PINK1 或 Parkin 的情况下,细胞通常会出现线粒体碎片化。虽然过度分裂可能导致细胞凋亡,但协调诱导分裂和自噬被认为有助于通过线粒体自噬清除受损的线粒体,在某些类型的细胞中已经观察到这种现象。在缺乏 PINK1 的小鼠中也可能发生代偿机制,与细胞和果蝇不同,这些小鼠只有轻微的线粒体功能障碍,并且缺乏多巴胺能神经元丢失。更好地了解线粒体动力学/周转率的特定变化与细胞死亡之间的关系,将有助于确定潜在的神经保护途径,引导 PINK1 缺陷细胞走向生存。未来,可以通过特定药物来操纵这些途径,以治疗 PD 以及其他可能具有异常线粒体功能和动力学的神经退行性疾病。
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