Disrupting the network of co-evolving amino terminal domain residues relieves mitochondrial calcium uptake inhibition by MCUb.

ABSTRACT: The regulatory mechanisms of the mitochondrial calcium uniporter complex (mtCU), the predominant channel mediating calcium (Ca^{2 +}) flux into the matrix, are critical for bioenergetics and cell fate. The pore-forming components of mtCU are the mitochondrial Ca²⁺ uniporter (MCU) subunit and the MCU dominant-negative beta (MCUb) subunit. Despite both MCU paralogs having conserved Asp-Ile-Met-Glu motifs responsible for Ca²⁺ selectivity, MCUb mediates only low Ca²⁺ conduction and has been characterized as an inhibitory subunit. We previously identified the MCU amino-terminal domain (NTD) as a negative feedback regulator of mtCU upon divalent cation binding but the role of the MCUb-NTD remains unknown. Thus, to gain mechanistic insight into

SUBMITTER: Colussi DM 

PROVIDER: S-EPMC11867204 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature