MECP2 Duplication Uncouples Mitochondrial and Purine Metabolism During neuronal maturation
Mitochondria and nucleotide metabolism are critical for cellular and developmental homeostasis, yet their potential interdependence and role in neurodevelopmental disease remain unclear. In <i>MECP2</i> Duplication Syndrome (MDS), we identify a conserved correlation between mitochondrial function and purine metabolism that is disrupted across human, organoid, and mouse models. Multiomics integration reveals Complex III as the focal point of mitochondrial collapse, leading to redox stress, DNA damage, and hyperactivation of the <i>de novo</i> purine biosynthesis via purinosome assembly. The breakdown of mitochondria-purinosome coupling compromises genome stability, impairs radial glia proliferation, and delays neuronal maturation. By linking a defined genetic dosage imbalance to metabolic network failure, our study positions the mitochondria-purinosome coordination as a fundamental control axis for neurodevelopment and a therapeutic entry point across metabolic and neurodevelopmental disorders.
Authors
- Joel Mathews (ORCID: https://orcid.org/0000-0002-5535-8080)
- Sergio Attanasio
- Huda Y. Zoghbi (ORCID: https://orcid.org/0000-0002-0700-3349)
- Davut Pehli̇van (ORCID: https://orcid.org/0000-0001-5788-0270)
- Christine M. Coquery
- Sara Bitar
- Luke Parkitny (ORCID: https://orcid.org/0000-0002-4473-0211)
- Guantong Qi
- John L. Hunyara (ORCID: https://orcid.org/0000-0002-7885-6525)
- Armand Soriano (ORCID: https://orcid.org/0009-0009-6619-6281)
- Sivan Osenberg
- Xuan Qin (ORCID: https://orcid.org/0000-0003-3728-5911)
- Jennifer L. Sheppard (ORCID: https://orcid.org/0000-0003-1830-0135)
- Yang Li (ORCID: https://orcid.org/0000-0001-9291-515X)
- Bernard Suter
- Senghong Sing
- Toni Claire Tacorda
- Saleh Mahmud Khalil
- Feng Li
- Gerarda Cappuccio
- George Timpone
- Paymaan Jafar-Nejad
- Demian Rocha Ifa
- Ashley Grace Anderson
- Hu Chen
- Mirjana Maletic-Savatic
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Baylor College of Medicine (US)
- Ionis Pharmaceuticals (United States) (US)
- Baylor School (US)
- Neurological Research Institute (US)
- Texas Children's Hospital (US)
- University of Houston (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-26
- DOI
- https://doi.org/10.64898/2025.12.24.696399
- Primary Topic
- Biochemical and Molecular Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00