MCUR1-CCDC90B complex is a conserved regulator of metabolic homeostasis

The mitochondrial calcium uniporter regulator 1 (MCUR1) is an evolutionarily conserved protein of the inner mitochondrial membrane whose physiological role remains elusive. Although initially proposed as a subunit of the mitochondrial calcium uniporter complex, emerging evidence suggests that MCUR1 has a broader functional outreach. Here, we identify a biallelic loss-of-function MCUR1 variant in a patient displaying neurological defects, which leads to loss of MCUR1 protein and exerts a dominant negative effect on its paralog CCDC90B. MCUR1 and CCDC90B form a stable hetero-oligomeric complex, whose stability depends on MCUR1. Despite preserved mitochondrial respiration, calcium uptake, and membrane potential, MCUR1-deficient human cells and yeast models exhibit impaired lipid and amino acid metabolism, leading to proliferative delay. Patient serum metabolomics confirm elevated amino acid levels, and yeast deletion mutants show nitrogen source-dependent growth defects that are rescued by human MCUR1 expression. These findings redefine the MCUR1-CCDC90B coiled-coil complex as a mitochondrial scaffold critical for membrane protein and metabolic homeostasis and suggest a potential link between MCUR1 deficiency and neurometabolic disease.