TY - JOUR
T1 - Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD
AU - Usui, Noriyoshi
AU - Doi, Miyuki
AU - Berto, Stefano
AU - Matsuoka, Kiwamu
AU - Ishida, Rio
AU - Miyauchi, Hana
AU - Fujiwara, Yuuki
AU - Irie, Koichiro
AU - Toritsuka, Michihiro
AU - Yamauchi, Takahira
AU - Hirai, Takaharu
AU - Xie, Min Jue
AU - Kayashima, Yoshinori
AU - Umeda, Naoko
AU - Iwata, Keiko
AU - Okumura, Kazuki
AU - Harada, Taeko
AU - Katayama, Taiichi
AU - Tsujii, Masatsugu
AU - Matsuzaki, Hideo
AU - Makinodan, Manabu
AU - Shimada, Shoichi
N1 - Publisher Copyright:
copyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc).
PY - 2026/4
Y1 - 2026/4
N2 - 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 copperHIF1α-BNIP3-mTOR signaling axis that links trace element imbalance to glial dysfunction and ASD-relevant behavioral phenotypes, providing mechanistic insight into neurodevelopment.
AB - 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 copperHIF1α-BNIP3-mTOR signaling axis that links trace element imbalance to glial dysfunction and ASD-relevant behavioral phenotypes, providing mechanistic insight into neurodevelopment.
UR - https://www.scopus.com/pages/publications/105034817912
UR - https://www.scopus.com/pages/publications/105034817912#tab=citedBy
U2 - 10.1126/sciadv.adz3398
DO - 10.1126/sciadv.adz3398
M3 - Article
C2 - 41920999
AN - SCOPUS:105034817912
SN - 2375-2548
VL - 12
JO - Science advances
JF - Science advances
IS - 14
M1 - eadz3398
ER -