Copper imbalance linked to white matter development and social behavior in autism－Study identifies a copper-HIF1α-BNIP3-mTOR pathway connecting trace elements to glial cell development－

June 03, 2026

Trace elements are needed only in small amounts, but they can have large effects on the developing brain. A research team led by Niigata University has now reported that copper, an essential trace element, may help connect metabolic changes in the body with white matter development and social behavior in autism spectrum disorder (ASD).

The study, published in Science Advances, combined human blood analysis, brain imaging, and mouse experiments. The team first measured 21 elements in plasma from people with ASD and typically developing controls. Among these elements, copper stood out because lower plasma copper levels were associated with higher scores on clinical measures of ASD symptoms. Brain MRI analysis also showed that people with ASD had reduced white matter volume, which was associated with social symptoms.

White matter is made largely of nerve fibers wrapped in myelin, an insulating layer that helps information travel efficiently through the brain. Myelin is produced by oligodendrocytes, a type of glial cell. “Our findings suggest that copper imbalance is not only a blood-based change but may be linked to how glial cells support brain circuit development,” says Professor Noriyoshi Usui of Niigata University.

To examine the mechanism, the researchers established a mouse model of developmental copper deficiency. These mice showed ASD-relevant behavioral changes, including altered social behavior and repetitive behaviors. In the brain, copper deficiency reduced oligodendrocyte-lineage cells, impaired their maturation, and decreased myelin formation.

Further analysis revealed a molecular pathway connecting copper deficiency to these changes. Copper deficiency disrupted HIF1α-related regulation of blood vessel formation and metabolic responses in the embryonic brain. This was followed by oxidative stress, mitochondrial dysfunction, and altered mitophagy, a quality-control process that removes damaged mitochondria. These changes increased BNIP3-mediated mitophagy and suppressed mTOR signaling, a pathway important for cell growth, metabolism, and oligodendrocyte development.

Importantly, activating mTOR signaling in the copper-deficient mouse model restored oligodendrocyte maturation and improved social behavior. However, the authors emphasize that these findings do not mean that copper supplementation should be considered a treatment for ASD. ASD is highly diverse, and copper levels may differ across individuals. Instead, the study provides a biological framework for understanding how trace element imbalance, mitochondrial regulation, and white matter development may interact during neurodevelopment.

Future work will examine whether trace element profiles, together with clinical and imaging data, can help clarify biological subgroups within ASD and support more precise evaluation of neurodevelopmental conditions. The study also highlights the importance of looking beyond neurons to understand how metabolism and glial cells shape brain function.

Publication Details

Journal:Science Advances
Title:Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD
Authors:Noriyoshi Usui*, Miyuki Doi, Stefano Berto, Kiwamu Matsuoka, Rio Ishida, Hana Miyauchi, Yuuki Fujiwara, Koichiro Irie, Michihiro Toritsuka, Takahira Yamauchi, Takaharu Hirai, Min-Jue Xie, Yoshinori Kayashima, Naoko Umeda, Keiko Iwata, Kazuki Okumura, Taeko Harada, Taiichi Katayama, Masatsugu Tsujii, Hideo Matsuzaki, Manabu Makinodan, Shoichi Shimada
*Corresponding Author
Doi: 10.1126/sciadv.adz3398

News release

The article was released in  EurekAlert, the online publication of the American Association for the Advancement of Science.

More News

All News