Starvation-induced metabolic rewiring affects mTORC1 composition in vivo
Abstract Lysosomes play a crucial role in metabolic adaptation to starvation, but detailed in vivo studies are scarce. Therefore, we investigated the changes of the proteome of liver lysosomes in mice starved short-term for 6h or long-term for 24h. We verified starvation-induced catabolism by weight...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-11-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-78873-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832571675770617856 |
|---|---|
| author | Edgar Kaade Simone Mausbach Nina Erps Marc Sylvester Farhad Shakeri Ron D. Jachimowicz Volkmar Gieselmann Melanie Thelen |
| author_facet | Edgar Kaade Simone Mausbach Nina Erps Marc Sylvester Farhad Shakeri Ron D. Jachimowicz Volkmar Gieselmann Melanie Thelen |
| author_sort | Edgar Kaade |
| collection | DOAJ |
| description | Abstract Lysosomes play a crucial role in metabolic adaptation to starvation, but detailed in vivo studies are scarce. Therefore, we investigated the changes of the proteome of liver lysosomes in mice starved short-term for 6h or long-term for 24h. We verified starvation-induced catabolism by weight loss, ketone body production, drop in blood glucose and an increase of 3-methylhistidine. Deactivation of mTORC1 in vivo after short-term starvation causes a depletion of mTORC1 and the associated Ragulator complex in hepatic lysosomes, resulting in diminished phosphorylation of mTORC1 target proteins. While mTORC1 lysosomal protein levels and activity in liver were restored after long-term starvation, the lysosomal levels of Ragulator remained constantly reduced. To determine whether this mTORC1 activity pattern may be organ-specific, we further investigated the key metabolic organs muscle and brain. mTORC1 inactivation, but not re-activation, occurred in muscle after a starvation of 12 h or longer. In brain, mTORC1 activity remained unchanged during starvation. As mTORC1 deactivation is known to induce autophagy, we further investigated the more than 150 non-lysosomal proteins enriched in the lysosomal fraction upon starvation. Proteasomal, cytosolic and peroxisomal proteins dominated after short-term starvation, while after long-term starvation, mainly proteasomal and mitochondrial proteins accumulated, indicating ordered autophagic protein degradation. |
| format | Article |
| id | doaj-art-b0b678d406df4061b74eba1374302f36 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-b0b678d406df4061b74eba1374302f362025-02-02T12:24:59ZengNature PortfolioScientific Reports2045-23222024-11-0114111510.1038/s41598-024-78873-7Starvation-induced metabolic rewiring affects mTORC1 composition in vivoEdgar Kaade0Simone Mausbach1Nina Erps2Marc Sylvester3Farhad Shakeri4Ron D. Jachimowicz5Volkmar Gieselmann6Melanie Thelen7Institute for Biochemistry and Molecular Biology, Medical Faculty, Rheinische Friedrich-Wilhelms-University of BonnInstitute for Biochemistry and Molecular Biology, Medical Faculty, Rheinische Friedrich-Wilhelms-University of BonnMax-Planck Institute for Biology of AgeingInstitute for Biochemistry and Molecular Biology, Medical Faculty, Rheinische Friedrich-Wilhelms-University of BonnInstitute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, Rheinische Friedrich-Wilhelms-University of BonnMax-Planck Institute for Biology of AgeingInstitute for Biochemistry and Molecular Biology, Medical Faculty, Rheinische Friedrich-Wilhelms-University of BonnInstitute for Biochemistry and Molecular Biology, Medical Faculty, Rheinische Friedrich-Wilhelms-University of BonnAbstract Lysosomes play a crucial role in metabolic adaptation to starvation, but detailed in vivo studies are scarce. Therefore, we investigated the changes of the proteome of liver lysosomes in mice starved short-term for 6h or long-term for 24h. We verified starvation-induced catabolism by weight loss, ketone body production, drop in blood glucose and an increase of 3-methylhistidine. Deactivation of mTORC1 in vivo after short-term starvation causes a depletion of mTORC1 and the associated Ragulator complex in hepatic lysosomes, resulting in diminished phosphorylation of mTORC1 target proteins. While mTORC1 lysosomal protein levels and activity in liver were restored after long-term starvation, the lysosomal levels of Ragulator remained constantly reduced. To determine whether this mTORC1 activity pattern may be organ-specific, we further investigated the key metabolic organs muscle and brain. mTORC1 inactivation, but not re-activation, occurred in muscle after a starvation of 12 h or longer. In brain, mTORC1 activity remained unchanged during starvation. As mTORC1 deactivation is known to induce autophagy, we further investigated the more than 150 non-lysosomal proteins enriched in the lysosomal fraction upon starvation. Proteasomal, cytosolic and peroxisomal proteins dominated after short-term starvation, while after long-term starvation, mainly proteasomal and mitochondrial proteins accumulated, indicating ordered autophagic protein degradation.https://doi.org/10.1038/s41598-024-78873-7 |
| spellingShingle | Edgar Kaade Simone Mausbach Nina Erps Marc Sylvester Farhad Shakeri Ron D. Jachimowicz Volkmar Gieselmann Melanie Thelen Starvation-induced metabolic rewiring affects mTORC1 composition in vivo Scientific Reports |
| title | Starvation-induced metabolic rewiring affects mTORC1 composition in vivo |
| title_full | Starvation-induced metabolic rewiring affects mTORC1 composition in vivo |
| title_fullStr | Starvation-induced metabolic rewiring affects mTORC1 composition in vivo |
| title_full_unstemmed | Starvation-induced metabolic rewiring affects mTORC1 composition in vivo |
| title_short | Starvation-induced metabolic rewiring affects mTORC1 composition in vivo |
| title_sort | starvation induced metabolic rewiring affects mtorc1 composition in vivo |
| url | https://doi.org/10.1038/s41598-024-78873-7 |
| work_keys_str_mv | AT edgarkaade starvationinducedmetabolicrewiringaffectsmtorc1compositioninvivo AT simonemausbach starvationinducedmetabolicrewiringaffectsmtorc1compositioninvivo AT ninaerps starvationinducedmetabolicrewiringaffectsmtorc1compositioninvivo AT marcsylvester starvationinducedmetabolicrewiringaffectsmtorc1compositioninvivo AT farhadshakeri starvationinducedmetabolicrewiringaffectsmtorc1compositioninvivo AT rondjachimowicz starvationinducedmetabolicrewiringaffectsmtorc1compositioninvivo AT volkmargieselmann starvationinducedmetabolicrewiringaffectsmtorc1compositioninvivo AT melaniethelen starvationinducedmetabolicrewiringaffectsmtorc1compositioninvivo |