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溶酶体脂质信号从外周向神经元传递，调节寿命。

Lysosome lipid signalling from the periphery to neurons regulates longevity.

机构信息

Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.

Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.

出版信息

Nat Cell Biol. 2022 Jun;24(6):906-916. doi: 10.1038/s41556-022-00926-8. Epub 2022 Jun 9.

DOI:10.1038/s41556-022-00926-8
PMID:35681008
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9203275/
Abstract

Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in ageing-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate ageing remains unclear. Here we report a fat-to-neuron lipid signalling pathway induced by lysosomal metabolism and its longevity-promoting role in Caenorhabditis elegans. We discovered that induced lysosomal lipolysis in peripheral fat storage tissue upregulates the neuropeptide signalling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation is mediated by a specific polyunsaturated fatty acid, dihomo-γ-linolenic acid, and LBP-3 lipid chaperone protein transported from the fat storage tissue to neurons. LBP-3 binds to dihomo-γ-linolenic acid, and acts through NHR-49 nuclear receptor and NLP-11 neuropeptide in neurons to extend lifespan. These results reveal lysosomes as a signalling hub to coordinate metabolism and ageing, and lysosomal signalling mediated inter-tissue communication in promoting longevity.

摘要

溶酶体是代谢细胞内外底物的关键细胞器。溶酶体代谢的改变与衰老相关的代谢和神经退行性疾病有关。然而，溶酶体代谢如何主动协调代谢和神经系统来调节衰老仍然不清楚。在这里，我们报告了一个由溶酶体代谢诱导的脂肪到神经元的脂质信号通路及其在秀丽隐杆线虫中的长寿促进作用。我们发现，外周脂肪储存组织中诱导的溶酶体脂肪分解上调了神经系统中的神经肽信号通路，从而促进了长寿。这种细胞非自主调节是由一种特定的多不饱和脂肪酸，二同型-γ-亚麻酸，和从脂肪储存组织运输到神经元的 LBP-3 脂质伴侣蛋白介导的。LBP-3 与二同型-γ-亚麻酸结合，并通过神经元中的 NHR-49 核受体和 NLP-11 神经肽发挥作用，从而延长寿命。这些结果揭示了溶酶体作为一个信号枢纽，协调代谢和衰老，以及溶酶体信号介导的组织间通讯促进长寿。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f07/9203275/7351933642ee/41556_2022_926_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f07/9203275/126e8ebd60e9/41556_2022_926_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f07/9203275/cae12b362ec0/41556_2022_926_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f07/9203275/685271b84f8b/41556_2022_926_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f07/9203275/011ea63a85fb/41556_2022_926_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f07/9203275/029d915fe7c4/41556_2022_926_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f07/9203275/ed1e390f21ca/41556_2022_926_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f07/9203275/38834b2a3f4b/41556_2022_926_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f07/9203275/bad7fcf003ae/41556_2022_926_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f07/9203275/25d2b68cbb9b/41556_2022_926_Fig15_ESM.jpg
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