Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104.
Department of Physics, University of California, San Diego, La Jolla, CA 92093.
Mol Biol Cell. 2022 Nov 1;33(13):ar123. doi: 10.1091/mbc.E22-03-0111. Epub 2022 Aug 31.
Macroautophagy is a homeostatic process required to clear cellular waste. Neuronal autophagosomes form constitutively in the distal tip of the axon and are actively transported toward the soma, with cargo degradation initiated en route. Cargo turnover requires autophagosomes to fuse with lysosomes to acquire degradative enzymes; however, directly imaging these fusion events in the axon is impractical. Here we use a quantitative model, parameterized and validated using data from primary hippocampal neurons, to explore the autophagosome maturation process. We demonstrate that retrograde autophagosome motility is independent of fusion and that most autophagosomes fuse with only a few lysosomes during axonal transport. Our results indicate that breakdown of the inner autophagosomal membrane is much slower in neurons than in nonneuronal cell types, highlighting the importance of this late maturation step. Together, rigorous quantitative measurements and mathematical modeling elucidate the dynamics of autophagosome-lysosome interaction and autophagosomal maturation in the axon.
自噬是一种维持细胞内稳态的过程，用于清除细胞废物。神经元自噬体在轴突的远端持续形成，并被主动运输到胞体，在运输过程中开始降解货物。货物的周转需要自噬体与溶酶体融合以获得降解酶；然而，直接在轴突中观察这些融合事件是不切实际的。在这里，我们使用一个定量模型，使用来自原代海马神经元的数据进行参数化和验证，来探索自噬体成熟过程。我们证明逆行自噬体的运动与融合无关，并且在轴突运输过程中，大多数自噬体仅与少数几个溶酶体融合。我们的结果表明，在神经元中，内自噬体膜的破裂速度比非神经元细胞类型慢得多，这突出了这个晚期成熟步骤的重要性。综上所述，严格的定量测量和数学建模阐明了轴突中自噬体-溶酶体相互作用和自噬体成熟的动力学。
