Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and restricted repetitive behaviors, yet the contribution of trace elements remains poorly defined. We profiled 21 trace elements in individuals with ASD and identified significantly reduced copper levels, which negatively correlated with social symptom severity. Magnetic resonance imaging revealed decreased white matter volume in ASD, which also correlated with social impairment. To explore the mechanisms, we generated a copper-deficient mouse model that displayed ASD-like behaviors and impaired oligodendrocyte (OL) development. Copper deficiency disrupted hypoxia-inducible factor 1α (HIF1α)-dependent angiogenesis and metabolic regulation in the embryonic brain, leading to oxidative stress, mitochondrial dysfunction, and BCL2 interacting protein 3 (BNIP3)-mediated mitophagy in oligodendrocyte progenitor cells. These processes suppressed mechanistic target of rapamycin kinase (mTOR) signaling, reduced OL-lineage cells, and caused hypomyelination. Restoring mTOR activity rescued OL maturation and improved social behavior in copper-deficient mice. These findings identify a copper-HIF1α-BNIP3-mTOR signaling axis that links trace element imbalance to glial dysfunction and ASD-relevant behavioral phenotypes, providing mechanistic insight into neurodevelopment.
Authors
- Naoko Umeda
- T. Hirai (ORCID: https://orcid.org/0000-0002-3307-8109)
- Shoichi Shimada (ORCID: https://orcid.org/0000-0001-5369-1069)
- Taiichi Katayama (ORCID: https://orcid.org/0000-0001-8137-0481)
- Stefano Berto (ORCID: https://orcid.org/0000-0001-9028-9458)
- Yuuki Fujiwara (ORCID: https://orcid.org/0000-0003-1032-7755)
- Rio Ishida
- Manabu Makinodan (ORCID: https://orcid.org/0000-0003-4339-9413)
- Noriyoshi Usui (ORCID: https://orcid.org/0000-0001-8079-8013)
- Miyuki Doi (ORCID: https://orcid.org/0009-0007-9847-1861)
- Yoshinori Kayashima
- Takahira Yamauchi (ORCID: https://orcid.org/0000-0001-9402-5062)
- Michihiro Toritsuka (ORCID: https://orcid.org/0000-0001-6891-4173)
- Min-Jue Xie
- Keiko Iwata (ORCID: https://orcid.org/0000-0001-9588-3106)
- Koichiro Irie
- Hana Miyauchi
- Masatsugu Tsujii
- Taeko Harada
- Hideo Matsuzaki
- Kazuki Okumura
Institutions
- University of Fukui (JP)
- Fujita Health University (JP)
- Medical University of South Carolina (US)
- Wakayama Medical University (JP)
- Hamamatsu University School of Medicine (JP)
- Osaka University Hospital (JP)
- Nara Medical University (JP)
- Niigata University (JP)
- Kumamoto University (JP)
- The University of Osaka (JP)
- Chukyo University (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1126/sciadv.adz3398
- Primary Topic
- Trace Elements in Health
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Naito Foundation
- Takeda Science Foundation
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- Hirose Foundation
- Foundation of Kinoshita Memorial Enterprise
- Inamori Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Osaka Medical Research Foundation for Intractable Diseases
- SENSHIN Medical Research Foundation
- Japan Society for the Promotion of Science
- Moonshot Research and Development Program