Choi, J. B. | bioRxiv Science

bioRxiv2026

Adrenomedullin Restores Mitochondrial Bioenergetics and Rescues Interneuron Phenotypes in Human Models of 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome, is the strongest genetic risk factor for schizophrenia, yet the cellular mechanisms underlying this vulnerability remain incompletely understood. Using iPSC-derived human subpallial organoids (hSOs) and forebrain assembloids (hFAs), we identified key 22q11.2DS cellular and molecular phenotypes in migrating cortical interneurons and rescued them with Adrenomedullin (ADM), a 52-amino-acid peptide hormone that acts through the CLR/RAMP2 receptor complex. Specifically, we discover that 22q11.2DS interneurons exhibit impaired migration patterns, and that this is associated with excessive mitochondrial fragmentation, reduced oxidative phosphorylation, and dysregulated calcium signaling. Transcriptomic analysis reveals a glycolytic shift and widespread downregulation of oxidative phosphorylation genes. Next, we identify ADM as a potent rescue agent that restores mitochondrial morphology, membrane potential, respiration, calcium homeostasis, actin retrograde flow, and interneuron migration. Mechanistically, we find that ADM signals through two parallel pathways: PKA-mediated DRP1 Ser637 phosphorylation, which promotes mitochondrial fusion, and PLC-mediated calcium signaling, which normalizes actin dynamics. These phenotypes and their rescue are recapitulated in primary developing human cortical tissue carrying the 22q11.2 deletion. Overall, our study establishes a mitochondrial-cytoskeletal axis as a novel biological mechanism underlying the alterations observed in neuronal development in human preclinical models of 22q11.2DS and identifies possible therapeutic molecular targets for 22q11.2DS-associated neuropsychiatric pathology. HIGHLIGHTSO_LIInhibitory neurons in 22q11.2DS organoids and assembloids show mitochondrial fragmentation and impaired migration C_LIO_LIADM rescues mitochondrial morphology, respiration, and interneuron migration C_LIO_LIPKA and PLC pathways mediate separate arms of ADMs rescue mechanism C_LIO_LIPhenotypes and ADM rescue are validated in human cortical tissue C_LI

neuroscience↗

bioRxiv2024

THE FAM53C/DYRK1A axis regulates the G1/S transition of the cell cycle

A growing number of therapies are being developed to target the cell cycle machinery for the treatment of cancer and other human diseases. Consequently, a greater understanding of the factors regulating cell cycle progression becomes essential to help enhance the response to these new therapies. Here, using data from the Cancer Dependency Map, we identified FAM53C as a new regulator of cell cycle progression. We found that FAM53C is critical for this cell cycle transition and that it acts upstream of the CyclinD-CDK4/6-RB axis and of p53 in the regulation of the G1/S transition. By mass spectrometry, biochemical, and cellular assays, we identified and validated DYRK1A as a cell cycle kinase that is inhibited by and directly interacts with FAM53C. Consistent with the role for FAM53C identified in cells in culture, FAM53C knockout human cortical organoids display increased cell cycle arrest and growth defects. Fam53C knockout mice show minor behavioral phenotypes. Because DYRK1A dysregulation contributes to developmental disorders such as Down syndrome as well as tumorigenesis, future strategies aiming at regulating FAM53C activity may benefit a broad range of patients.

cell biology↗