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Peer-reviewedCC BY 4.0Proceedings of the National Academy of Sciences of the United States of America

Stress-inducible WASF3 regulates brain metabolism and cognitive function

  • Abu M. Syed1
  • Jin Ma1
  • Ping-yuan Wang1
  • Youlim Son1
  • Rozhin Penjweini2
  • Nikhil Mattu2
  • Jay R. Knutson2
  • Sachiko Nakamori-Yamashita3
  • Danielle A. Springer3
  • Ananya Ganguly1
  • Chengyu Liu4
  • Paul M. Hwang1
4 affiliations
  1. 1Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
  2. 2Laboratory of Advanced Microscopy and Biophotonics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
  3. 3Murine Phenotyping Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
  4. 4Transgenic Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
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Abstract

Wiskott–Aldrich syndrome protein family member 3 (WASF3) disrupts mitochondrial respiration and is induced in association with endoplasmic reticulum stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Because cognitive impairment is a hallmark of ME/CFS, we investigated the role of WASF3 in brain metabolism and function using WASF3 transgenic and knockout mouse models. WASF3 disrupted respiratory complex IV and localized to mitochondria-associated membranes, known to modulate cellular processes important for neuronal activity. Overexpression of WASF3 in the hippocampus, a critical region for memory formation, induced a metabolic shift toward glycolysis and promoted a “hypometabolic” state. Increased WASF3 also caused a reduction in ATPIF1, previously shown to facilitate cognitive function, and impaired learning. Conversely, WASF3 deficiency increased ATPIF1 level, enhanced oxidative metabolism, and preserved cognitive function under stress. Together, these findings demonstrate that WASF3 suppresses oxidative metabolism in the brain and contributes to cognitive dysfunction, providing mechanistic insights into the “brain fog” reported in ME/CFS.

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Cite

BibTeXRIS
BibTeX
@article{syed2026stressinducible,
  title = {{Stress-inducible WASF3 regulates brain metabolism and cognitive function}},
  author = {Abu M. Syed and Jin Ma and Ping-yuan Wang and Youlim Son and Rozhin Penjweini and Nikhil Mattu and Jay R. Knutson and Sachiko Nakamori-Yamashita and Danielle A. Springer and Ananya Ganguly and Chengyu Liu and Paul M. Hwang},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2617198123},
  url = {https://doi.org/10.1073/pnas.2617198123},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Stress-inducible WASF3 regulates brain metabolism and cognitive function
AU  - Abu M. Syed
AU  - Jin Ma
AU  - Ping-yuan Wang
AU  - Youlim Son
AU  - Rozhin Penjweini
AU  - Nikhil Mattu
AU  - Jay R. Knutson
AU  - Sachiko Nakamori-Yamashita
AU  - Danielle A. Springer
AU  - Ananya Ganguly
AU  - Chengyu Liu
AU  - Paul M. Hwang
PY  - 2026
DA  - 2026/10/27
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2617198123
UR  - https://doi.org/10.1073/pnas.2617198123
AB  - Wiskott–Aldrich syndrome protein family member 3 (WASF3) disrupts mitochondrial respiration and is induced in association with endoplasmic reticulum stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Because cognitive impairment is a hallmark of ME/CFS, we investigated the role of WASF3 in brain metabolism and function using WASF3 transgenic and knockout mouse models. WASF3 disrupted respiratory complex IV and localized to mitochondria-associated membranes, known to modulate cellular processes important for neuronal activity. Overexpression of WASF3 in the hippocampus, a critical region for memory formation, induced a metabolic shift toward glycolysis and promoted a “hypometabolic” state. Increased WASF3 also caused a reduction in ATPIF1, previously shown to facilitate cognitive function, and impaired learning. Conversely, WASF3 deficiency increased ATPIF1 level, enhanced oxidative metabolism, and preserved cognitive function under stress. Together, these findings demonstrate that WASF3 suppresses oxidative metabolism in the brain and contributes to cognitive dysfunction, providing mechanistic insights into the “brain fog” reported in ME/CFS.
SN  - 0027-8424
SN  - 1091-6490
ER  -