Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Cells. 2023 Oct 20;12(20):2496. doi: 10.3390/cells12202496.
Mitochondrial dysfunction in astrocytes has been implicated in the development of various neurological disorders. Mitophagy, mitochondrial autophagy, is required for proper mitochondrial function by preventing the accumulation of damaged mitochondria. The importance of mitophagy, specifically in the astrocytes of the optic nerve (ON), has been little studied. We introduce an animal model in which two separate mutations act synergistically to produce severe ON degeneration. The first mutation is in , which encodes βA3/A1-crystallin, a lens protein also expressed in astrocytes, where it regulates lysosomal pH. The second mutation is in , which encodes branched-chain ketoacid dehydrogenase kinase, which is ubiquitously expressed in the mitochondrial matrix and involved in the catabolism of the branched-chain amino acids. BCKDK is essential for mitochondrial function and the amelioration of oxidative stress. Neither of the mutations in isolation has a significant effect on the ON, but animals homozygous for both mutations (DM) exhibit very serious ON degeneration. ON astrocytes from these double-mutant (DM) animals have lysosomal defects, including impaired mitophagy, and dysfunctional mitochondria. Urolithin A can rescue the mitophagy impairment in DM astrocytes and reduce ON degeneration. These data demonstrate that efficient mitophagy in astrocytes is required for ON health and functional integrity.
星形胶质细胞中线粒体功能障碍与各种神经退行性疾病的发展有关。线粒体自噬（mitophagy）是一种通过防止受损线粒体的积累来维持正常线粒体功能所必需的过程。线粒体自噬在视神经（ON）星形胶质细胞中的重要性尚未得到充分研究。我们引入了一种动物模型，其中两种单独的突变协同作用导致严重的 ON 变性。第一个突变位于 ，编码βA3/A1-晶体蛋白，这是一种晶状体蛋白，也在星形胶质细胞中表达，在那里它调节溶酶体 pH 值。第二个突变位于 ，编码支链酮酸脱氢酶激酶，该酶在整个线粒体基质中广泛表达，参与支链氨基酸的分解代谢。BCDK 对于线粒体功能和氧化应激的缓解是必不可少的。单独的突变都不会对 ON 产生显著影响，但同时携带这两种突变的动物（DM）表现出非常严重的 ON 变性。来自这些双突变（DM）动物的 ON 星形胶质细胞存在溶酶体缺陷，包括受损的线粒体自噬和功能失调的线粒体。尿石素 A 可以挽救 DM 星形胶质细胞中的线粒体自噬缺陷并减少 ON 变性。这些数据表明，星形胶质细胞中线粒体自噬的效率对于 ON 的健康和功能完整性是必需的。
