HUWE1 Targets Mitochondria via RMC1 to Promote Neurodevelopment

ABSTRACT: The HECT-type E3 ubiquitin ligase HUWE1 is a critical regulator of protein homeostasis, genome stability, and neurodevelopment. Variants in HUWE1 are linked to X-linked intellectual disability (XLID), yet a significant number of HUWE1 variants are noncatalytic, leaving their disease mechanisms unresolved. Here, we identify a HUWE1-RMC1 axis that specifically directs HUWE1 ubiquitin signaling to mitochondria to govern neural development. In zebrafish, noncatalytic HUWE1 variants found in XLID patients (M375I, G660R, H669Q) recapitulate key neurodevelopmental deficits, including impaired brain growth and motor neuron defects. Global ubiquitin profiling reveals that these variants selectively disrupt the ubiquitination of mitochondrial proteins without affecting nuclear substrates. Mechanistically, HUWE1 is recruited to mitochondria via direct interaction with the RMC1 subunit of the Mon1-Ccz1-RMC1 complex. HUWE1 depends on this interaction to modify mitochondrial substrates, and XLID-associated variants disrupt this step, preventing HUWE1 recruitment and impairing mitochondrial substrate ubiquitination. Notably, pharmacological activation of mitophagy with Urolithin A ameliorates neurodevelopmental phenotypes in HUWE1-deficient zebrafish. Our work defines RMC1 as a mitochondrial adaptor that spatially constrains HUWE1 activity, provides a molecular rationale for noncatalytic HUWE1 variants in XLID, and nominates mitophagy enhancement as a therapeutic strategy for disorders of mitochondrial ubiquitination.

ORGANISM(S): Homo Sapiens

SUBMITTER: Da Jia  

PROVIDER: PXD080345 | iProX | Mon Jun 29 00:00:00 BST 2026

REPOSITORIES: iProX