MCUR1–CCDC90B complex is a conserved mitochondrial scaffold regulating metabolic homeostasis

The mitochondrial calcium uniporter regulator 1 (MCUR1) is an evolutionarily conserved protein of the inner mitochondrial membrane ¹ , yet its physiological role has remained elusive. Although initially proposed to function as a subunit of the mitochondrial calcium uniporter complex (MCUC) ^2–4 , emerging evidence suggests that MCUR1 has a broader functional spectrum ^5–7 . Here, we identify a biallelic loss-of-function MCUR1 variant (c.802C>T; p.R268X) in a patient with a progressive neurological phenotype. This mutation leads to loss of MCUR1 protein and exerts a dominant-negative effect on its paralog, CCDC90B. We show that MCUR1 and CCDC90B form a hetero-oligomeric complex whose stability depends on MCUR1. Deletion of MCUR1 and CCDC90B in the fission yeast Schizosaccharomyces pombe , which lacks the MCUC, impairs lipid and amino acid metabolism and causes nitrogen source-dependent growth defects that are rescued by expression of human MCUR1. Patient serum metabolomics confirms an imbalance in the amino acid pool, while MCUR1 deficiency in patient-derived skin fibroblasts upregulates autophagy, perturbs non-essential amino acid metabolism, and limits biosynthetic capacity, resulting in delayed proliferation and migration. These findings redefine the MCUR1–CCDC90B coiled-coil complex as a transmembrane scaffold critical for the integrity of mitochondrial protein complexes and the maintenance of metabolic homeostasis, suggesting a potential link between MCUR1 deficiency and human neurometabolic disease.