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

Author

Listed:
  • 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
    Middleton Memorial Veterans Hospital)

  • Rozalyn M. Anderson

    (University of Wisconsin Madison
    Middleton Memorial Veterans Hospital)

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.

Suggested Citation

  • 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, 2025. "Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57363-y
    DOI: 10.1038/s41467-025-57363-y
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    References listed on IDEAS

    as
    1. Vera Gorbunova & Andrei Seluanov & Paolo Mita & Wilson McKerrow & David Fenyö & Jef D. Boeke & Sara B. Linker & Fred H. Gage & Jill A. Kreiling & Anna P. Petrashen & Trenton A. Woodham & Jackson R. Ta, 2021. "The role of retrotransposable elements in ageing and age-associated diseases," Nature, Nature, vol. 596(7870), pages 43-53, August.
    2. Simeon R. Mihaylov & Lydia M. Castelli & Ya-Hui Lin & Aytac Gül & Nikita Soni & Christopher Hastings & Helen R. Flynn & Oana Păun & Mark J. Dickman & Ambrosius P. Snijders & Robert Goldstone & Oliver, 2023. "The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
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