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

Journal Proc. Natl. Acad. Sci. U. S. A. 120(39):e2221553120. (2023)
Title Neuronal MML-1/MXL-2 regulates systemic aging via glutamate transporter and cell non-autonomous autophagic and peroxidase activity
Laboratory Laboratory of Intracellular Membrane Dynamics〈Prof. YOSHIMORI Tamotsu〉
Abstract

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.

Authors

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)

  1. Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
  2. Department of Neurology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  3. Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
  4. Graduate School of Life Science and Technology, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
  5. Department of Cellular Physiology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
  6. Department of Life Science, Rikkyo University, Tokyo 171-8501, Japan.
  7. Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
  8. Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University of Cologne, Cologne 50931, Germany.
  9. Department of Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  10. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan.
  11. Institute for Advanced Co-Creation Studies, Osaka University, Osaka 565-0871, Japan.
PubMed 37722055

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