Organelle proteomic profiling reveals lysosomal heterogeneity in association with longevity
- Xiamen University, China
- Baylor College of Medicine, HHMI, United States
- Baylor College of Medicine, United States
- Independent, United States
- Stanford University, United States
Abstract
Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins associated with the lysosome mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked to longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using deep proteomic profiling, we systemically profiled lysosome-associated proteins linked with four different longevity mechanisms. We discovered the lysosomal recruitment of AMPK and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we further elucidated lysosomal heterogeneity across tissues as well as the increased enrichment of the Ragulator complex on Cystinosin positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity across multiple scales and provides resources for understanding the contribution of lysosomal protein dynamics to signal transduction, organelle crosstalk and organism longevity.
Data availability
The mass spectrometry data for protein identification have been deposited via the MASSIVE repository (MSV000090909) to the Proteome X change Consortium (http://proteomecentral.proteomexchange.org) with the dataset identifier PXD038865.Analysis code for Figure 6D, 6F and Figure 6-figure supplement 1 is included in the Supplementary code.
-
Organelle proteomic profiling reveals lysosomal heterogeneity in association with longevityProteome Xchange Consortium, PXD038865.
Article and author information
Author details
Funding
Howard Hughes Medical Institute
- Meng C Wang
National Natural Science Foundation of China (32071146)
- Yong Yu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2024, Yu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,152
- views
-
- 729
- downloads
-
- 5
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Organelle proteomic profiling reveals lysosomal heterogeneity in association with longevity
eLife 13:e85214.
https://doi.org/10.7554/eLife.85214
Further reading
-
- Cell Biology
Cytoskeleton rearrangements promote formation of a giant structure called a GUVac that stops cells from dying when they become detached from the extracellular matrix.
-
- Cell Biology
- Neuroscience
Astrocytes are active cells involved in brain function through the bidirectional communication with neurons, in which astrocyte calcium plays a crucial role. Synaptically evoked calcium increases can be localized to independent subcellular domains or expand to the entire cell, i.e., calcium surge. Because a single astrocyte may contact ~100,000 synapses, the control of the intracellular calcium signal propagation may have relevant consequences on brain function. Yet, the properties governing the spatial dynamics of astrocyte calcium remains poorly defined. Imaging subcellular responses of cortical astrocytes to sensory stimulation in mice, we show that sensory-evoked astrocyte calcium responses originated and remained localized in domains of the astrocytic arborization, but eventually propagated to the entire cell if a spatial threshold of >23% of the arborization being activated was surpassed. Using Itpr2-/- mice, we found that type-2 IP3 receptors were necessary for the generation of astrocyte calcium surge. We finally show using in situ electrophysiological recordings that the spatial threshold of the astrocyte calcium signal consequently determined the gliotransmitter release. Present results reveal a fundamental property of astrocyte physiology, i.e., a spatial threshold for astrocyte calcium propagation, which depends on astrocyte intrinsic properties and governs astrocyte integration of local synaptic activity and subsequent neuromodulation.
