Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD PMID: 41920999

Target-related Cytokines

2026-09-23

Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD

Sci Adv. 2026 Apr 3;12(14):eadz3398. doi: 10.1126/sciadv.adz3398.

Noriyoshi Usui ¹ ² ³ ⁴ ⁵ ⁶ , Miyuki Doi ¹ ² ⁶ , Stefano Berto ⁷ , Kiwamu Matsuoka ⁸ , Rio Ishida ⁸ ⁹ ¹⁰ , Hana Miyauchi ² , Yuuki Fujiwara ⁴ , Koichiro Irie ² , Michihiro Toritsuka ⁹ ¹⁰ ¹¹ , Takahira Yamauchi ⁸ , Takaharu Hirai ¹² ¹³ , Min-Jue Xie ⁴ ¹³ ¹⁴ , Yoshinori Kayashima ⁸ , Naoko Umeda ¹⁴ ¹⁵ , Keiko Iwata ⁴ ¹⁴ ¹⁶ , Kazuki Okumura ⁸ , Taeko Harada ¹⁷ , Taiichi Katayama ⁴ , Masatsugu Tsujii ¹⁸ , Hideo Matsuzaki ⁴ ¹³ ¹⁴ , Manabu Makinodan ⁹ ¹⁰ ¹¹ , Shoichi Shimada ² ⁴ ⁵ ⁶

Affiliations

1. Department of Developmental Neuroscience, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
2. Department of Neuroscience and Cell Biology, Graduate School of Medicine, The University of Osaka, Suita 565-0871, Japan.
3. Omics Center, Center of Medical Innovation and Translational Research, Graduate School of Medicine, The University of Osaka, Suita 565-0871, Japan.
4. United Graduate School of Child Development, The University of Osaka, Suita 565-0871, Japan.
5. Global Center for Medical Engineering and Informatics, The University of Osaka, Suita 565-0871, Japan.
6. Addiction Research Unit, Osaka Psychiatric Research Center, Osaka Psychiatric Medical Center, Osaka 541-8567, Japan.
7. Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29403, USA.
8. Department of Psychiatry, Nara Medical University, Nara 634-8522, Japan.
9. Division of Transformative Psychiatry and Synergistic Research, International Center for Brain Sciences, Fujita Health University, Aichi 470-1192, Japan.
10. Department of Psychiatry, Fujita Health University, Aichi 470-1192, Japan.
11. Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
12. Department of Psychiatric and Mental Health Nursing, School of Nursing, University of Fukui, Fukui 910-1193, Japan.
13. Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan.
14. Division of Development of Mental Functions, Research Center for Child Mental Development, University of Fukui, Fukui 910-1193, Japan.
15. Department of Maternal and Child Health Nursing, School of Nursing, University of Fukui, Fukui 910-1193, Japan.
16. Laboratory of Pharmacology, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama 640-8156, Japan.
17. Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
18. School of Contemporary Sociology, Chukyo University, Aichi 470-0393, Japan.

Abstract

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.