<br>神经元 MML-1/MXL-2 通过谷氨酸转运蛋白和细胞非自主自噬和过氧化物酶活性调节全身衰老,Proceedings of the National Academy of Sciences of the United States of America

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神经元 MML-1/MXL-2 通过谷氨酸转运蛋白和细胞非自主自噬和过氧化物酶活性调节全身衰老
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2023-09-18 , DOI: 10.1073/pnas.2221553120
Tatsuya Shioda ₁ , Ittetsu Takahashi ₁ , Kensuke Ikenaka ₂ , Naonobu Fujita _{3,

4} , Tomotake Kanki ₅ , Toshihiko Oka ₆ , Hideki Mochizuki ₂ , Adam Antebi _{7,

8} , Tamotsu Yoshimori _{1,

9,

10} , Shuhei Nakamura _{1,

9,

11}

Affiliation

Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
Department of Neurology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
Graduate School of Life Science and Technology, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
Department of Cellular Physiology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
Department of Life Science, Rikkyo University, Tokyo 171-8501, Japan.
Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University of Cologne, Cologne 50931, Germany.
Department of Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan.
Institute for Advanced Co-Creation Studies, Osaka University, Osaka 565-0871, Japan.

越来越多的证据表明存在调节系统衰老的组织间通讯，但潜在的分子网络尚未得到充分探索。我们和其他人之前表明，两种基本的螺旋-环-螺旋转录因子，MML-1和HLH-30，是几种长寿范例（包括无种系秀丽隐杆线虫）的寿命延长所必需的。然而，尚不清楚这些因子针对哪些组织来促进长寿。在这里，通过组织特异性敲低实验，我们发现 MML-1 及其异二聚体伙伴 MXL-2 和 HLH-30 主要作用于神经元，以延长无种系动物的寿命。然而有趣的是，神经元中 MML-1 的下游级联与 HLH-30 的下游级联不同。基于神经元 RNA 干扰 (RNAi) 的转录组分析表明，谷氨酸转运蛋白 GLT-5 是 MML-1 的下游靶标，但不是 HLH-30。此外，在长寿动物中，神经元中的 MML-1-GTL-5 轴对于防止年龄依赖性蛋白质稳态崩溃以及分别通过自噬和过氧化物酶 MLT-7 增加氧化应激至关重要。总的来说，我们的研究表明，系统性衰老是由涉及神经和外周组织中神经元 MML-1 功能的分子网络调节的。

"点击查看英文标题和摘要"

Neuronal MML-1/MXL-2 regulates systemic aging via glutamate transporter and cell nonautonomous autophagic and peroxidase activity

Accumulating evidence has demonstrated the presence of intertissue-communication regulating systemic aging, but the underlying molecular network has not been fully explored. We and others previously showed that two basic helix–loop–helix transcription factors, MML-1 and HLH-30, are required for lifespan extension in several longevity paradigms, including germlineless Caenorhabditis elegans . However, it is unknown what tissues these factors target to promote longevity. Here, using tissue-specific knockdown experiments, we found that MML-1 and its heterodimer partners MXL-2 and HLH-30 act primarily in neurons to extend longevity in germlineless animals. Interestingly, however, the downstream cascades of MML-1 in neurons were distinct from those of HLH-30. Neuronal RNA interference (RNAi)-based transcriptome analysis revealed that the glutamate transporter GLT-5 is a downstream target of MML-1 but not HLH-30. Furthermore, the MML-1-GTL-5 axis in neurons is critical to prevent an age-dependent collapse of proteostasis and increased oxidative stress through autophagy and peroxidase MLT-7, respectively, in long-lived animals. Collectively, our study revealed that systemic aging is regulated by a molecular network involving neuronal MML-1 function in both neural and peripheral tissues.

更新日期：2023-09-18

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