Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging
Abstract The brain is a high-energy tissue, and although aging is associated with dysfunctional inflammatory and neuron-specific functional pathways, a direct connection to metabolism is not established. Here, we show that isoforms of mitochondrial regulator PGC-1α are driven from distinct brain cel...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57363-y |
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| author | Dylan C. Souder Eric R. McGregor Josef P. Clark Timothy W. Rhoads Tiaira J. Porter Kevin W. Eliceiri Darcie L. Moore Luigi Puglielli Rozalyn M. Anderson |
| author_facet | Dylan C. Souder Eric R. McGregor Josef P. Clark Timothy W. Rhoads Tiaira J. Porter Kevin W. Eliceiri Darcie L. Moore Luigi Puglielli Rozalyn M. Anderson |
| author_sort | Dylan C. Souder |
| collection | DOAJ |
| description | Abstract The brain is a high-energy tissue, and although aging is associated with dysfunctional inflammatory and neuron-specific functional pathways, a direct connection to metabolism is not established. Here, we show that isoforms of mitochondrial regulator PGC-1α are driven from distinct brain cell-type specific promotors, repressed with aging, and integral in coordinating metabolism and growth signaling. Transcriptional and proteomic profiles of cortex from male adult, middle age, and advanced age mice reveal an aging metabolic signature linked to PGC-1α. In primary culture, a neuron-exclusive promoter produces the functionally dominant isoform of PGC-1α. Using growth repression as a challenge, we find that PGC-1α is regulated downstream of GSK3β independently across promoters. Broad cellular metabolic consequences of growth inhibition observed in vitro are mirrored in vivo, including activation of PGC-1α directed programs and suppression of aging pathways. These data place PGC-1α centrally in a growth and metabolism network directly relevant to brain aging. |
| format | Article |
| id | doaj-art-a4106157f90c4b5a9e41cba47c30759a |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a4106157f90c4b5a9e41cba47c30759a2025-08-20T02:59:32ZengNature PortfolioNature Communications2041-17232025-02-0116111810.1038/s41467-025-57363-yNeuron-specific isoform of PGC-1α regulates neuronal metabolism and brain agingDylan C. Souder0Eric R. McGregor1Josef P. Clark2Timothy W. Rhoads3Tiaira J. Porter4Kevin W. Eliceiri5Darcie L. Moore6Luigi Puglielli7Rozalyn M. Anderson8Department of Medicine, SMPH, University of Wisconsin MadisonDepartment of Medicine, SMPH, University of Wisconsin MadisonDepartment of Medicine, SMPH, University of Wisconsin MadisonDepartment of Nutritional Sciences, University of Wisconsin MadisonDepartment of Neuroscience, University of Wisconsin MadisonDepartment of Medical Physics, University of Wisconsin MadisonDepartment of Neuroscience, University of Wisconsin MadisonDepartment of Medicine, SMPH, University of Wisconsin MadisonDepartment of Medicine, SMPH, University of Wisconsin MadisonAbstract The brain is a high-energy tissue, and although aging is associated with dysfunctional inflammatory and neuron-specific functional pathways, a direct connection to metabolism is not established. Here, we show that isoforms of mitochondrial regulator PGC-1α are driven from distinct brain cell-type specific promotors, repressed with aging, and integral in coordinating metabolism and growth signaling. Transcriptional and proteomic profiles of cortex from male adult, middle age, and advanced age mice reveal an aging metabolic signature linked to PGC-1α. In primary culture, a neuron-exclusive promoter produces the functionally dominant isoform of PGC-1α. Using growth repression as a challenge, we find that PGC-1α is regulated downstream of GSK3β independently across promoters. Broad cellular metabolic consequences of growth inhibition observed in vitro are mirrored in vivo, including activation of PGC-1α directed programs and suppression of aging pathways. These data place PGC-1α centrally in a growth and metabolism network directly relevant to brain aging.https://doi.org/10.1038/s41467-025-57363-y |
| spellingShingle | Dylan C. Souder Eric R. McGregor Josef P. Clark Timothy W. Rhoads Tiaira J. Porter Kevin W. Eliceiri Darcie L. Moore Luigi Puglielli Rozalyn M. Anderson Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging Nature Communications |
| title | Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging |
| title_full | Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging |
| title_fullStr | Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging |
| title_full_unstemmed | Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging |
| title_short | Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging |
| title_sort | neuron specific isoform of pgc 1α regulates neuronal metabolism and brain aging |
| url | https://doi.org/10.1038/s41467-025-57363-y |
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