A comparative map of macroautophagy and mitophagy in the vertebrate eye

Photoreception is pivotal to our experience and perception of the natural world; hence the eye is of prime importance for most vertebrate animals to sense light. Central to visual health is mitochondrial homeostasis, and the selective autophagic turnover of mitochondria (mitophagy) is predicted to play a key role here. Despite studies that link aberrant mitophagy to ocular dysfunction, little is known about the prevalence of basal mitophagy, or its relationship to general autophagy, in the visual system. In this study, we utilize the mito-QC mouse and a closely related general macroautophagy reporter model to profile basal mitophagy and macroautophagy in the adult and developing eye. We report that ocular macroautophagy is widespread, but surprisingly mitophagy does not always follow the same pattern of occurrence. We observe low levels of mitophagy in the lens and ciliary body, in stark contrast to the high levels of general MAP1LC3-dependent macroautophagy in these regions. We uncover a striking reversal of this process in the adult retina, where mitophagy accounts for a larger degree of the macroautophagy taking place, specifically in the photoreceptor neurons of the outer nuclear layer. We also show the developmental regulation of autophagy in a variety of ocular tissues. In particular, mitophagy in the adult mouse retina is reversed in localization during the latter stages of development. Our work thus defines the landscape of mitochondrial homeostasis in the mammalian eye, and in doing so highlights the selective nature of autophagy in vivo and the specificity of the reporters used. Abbreviations: ATG: autophagy related; GFP: green fluorescent protein; LC3: microtubule associated protein 1 light chain 3; ONH: optic nerve head; ONL: outer nuclear layer; RPE: retinal pigment epithelium.

光感知对于人类感知与体验自然世界至关重要，因此眼睛对于绝大多数脊椎动物感知光线而言具有核心意义。视觉健康的核心在于线粒体稳态，而线粒体的选择性自噬周转（mitophagy，线粒体自噬）被认为在此过程中发挥关键作用。尽管已有研究将异常线粒体自噬与眼部功能障碍相关联，但目前对于视觉系统中基础线粒体自噬的发生频率，及其与常规自噬的关联仍知之甚少。本研究使用mito-QC小鼠及一种与之密切相关的常规巨自噬报告基因模型，对成年与发育中的眼部组织内的基础线粒体自噬与巨自噬进行全景式分析。本研究发现眼部巨自噬广泛存在，但令人意外的是，线粒体自噬的发生模式并非始终与之保持一致。我们观察到晶状体与睫状体内线粒体自噬水平较低，与这些区域中高水平的、依赖微管相关蛋白1轻链3（MAP1LC3）的常规巨自噬形成鲜明对比。我们在成年视网膜中发现了这一模式的显著逆转：线粒体自噬在总巨自噬中占比更高，这一现象尤其见于外核层的感光神经元中。此外，我们还阐明了多种眼部组织中自噬的发育调控机制。具体而言，成年小鼠视网膜内的线粒体自噬在发育后期发生了定位模式的逆转。因此，本研究明确了哺乳动物眼部线粒体稳态的整体特征，并借此凸显了体内自噬的选择性本质以及所使用报告基因的特异性。缩略语说明：ATG：自噬相关基因；GFP：绿色荧光蛋白；LC3：微管相关蛋白1轻链3；ONH：视神经乳头；ONL：外核层；RPE：视网膜色素上皮。