1. The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development
- Author
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Fuchen Liu, Luis Varela, Alice M. Giani, André M. M. Sousa, Tamas L. Horvath, Giuseppe Merla, Paolo Prontera, Amy F.T. Arnsten, Matija Sestan-Pesa, Jae Eun Song, Andrew T.N. Tebbenkamp, Jinmyung Choi, Candace Bichsel, Marina R. Picciotto, Zhuo Li, Constantinos D. Paspalas, Nenad Sestan, Daniel Franjic, Marco Koch, Miguel I. Paredes, Klara Szigeti-Buck, Yann S. Mineur, Yuka Imamura Kawasawa, Mingfeng Li, Zhong-Wu Liu, Tebbenkamp, Atn, Varela, L, Choi, J, Paredes, Mi, Giani, Am, Song, Je, Sestan-Pesa, M, Franjic, D, Sousa, Amm, Liu, Zw, Li, Mf, Bichsel, C, Koch, M, Szigeti-Buck, K, Liu, Fc, Li, Z, Kawasawa, Yi, Paspalas, Cd, Mineur, Y, Prontera, P, Merla, G, Picciotto, Mr, Arnsten, Aft, Horvath, Tl, and Sestan, N
- Subjects
0301 basic medicine ,Male ,Williams Syndrome ,Oxidative phosphorylation ,Mitochondrion ,General Biochemistry, Genetics and Molecular Biology ,Oxidative Phosphorylation ,Article ,03 medical and health sciences ,Mice ,medicine ,Animals ,Humans ,Gene ,Cells, Cultured ,ATP synthase ,biology ,HEK 293 cells ,Brain ,HSP40 Heat-Shock Proteins ,medicine.disease ,Phenotype ,Macaca mulatta ,Cell biology ,Mitochondria ,ATP Synthetase Complexes ,Mice, Inbred C57BL ,030104 developmental biology ,HEK293 Cells ,biology.protein ,Female ,Williams syndrome ,Function (biology) - Abstract
Summary Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene’s contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.
- Published
- 2018