Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging

Dylan C. Souder, Eric R. McGregor, Josef P. Clark, Timothy W. Rhoads, Tiaira J. Porter, Kevin W. Eliceiri, Darcie L. Moore, Luigi Puglielli and Rozalyn M. Anderson ()
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Dylan C. Souder: University of Wisconsin Madison
Eric R. McGregor: University of Wisconsin Madison
Josef P. Clark: University of Wisconsin Madison
Timothy W. Rhoads: University of Wisconsin Madison
Tiaira J. Porter: University of Wisconsin Madison
Kevin W. Eliceiri: University of Wisconsin Madison
Darcie L. Moore: University of Wisconsin Madison
Luigi Puglielli: University of Wisconsin Madison
Rozalyn M. Anderson: University of Wisconsin Madison

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57363-y

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