Recently identified core proteins (MICU1, MCU, EMRE) forming the mitochondrial Ca uniporter complex propelled investigations into its physiological workings. Here, we apply structured illumination microscopy to visualize and localize these proteins in living cells. Our data show that MICU1 localizes at the inner boundary membrane (IBM) due to electrostatic interaction of its polybasic domain. Moreover, this exclusive localization of MICU1 is important for the stability of cristae junctions (CJ), cytochrome c release and mitochondrial membrane potential. In contrast to MICU1, MCU and EMRE are homogeneously distributed at the inner mitochondrial membrane under resting conditions. However, upon Ca elevation MCU and EMRE dynamically accumulate at the IBM in a MICU1-dependent manner. Eventually, our findings unveil an essential function of MICU1 in CJ stabilization and provide mechanistic insights of how sophistically MICU1 controls the MCU-Complex while maintaining the structural mitochondrial membrane framework.
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http://dx.doi.org/10.1038/s41467-019-11692-x | DOI Listing |
J Biol Chem
January 2025
Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22903. Electronic address:
The mitochondrial Ca uniporter is the Ca channel responsible for mitochondrial Ca uptake. It plays crucial physiological roles in regulating oxidative phosphorylation, intracellular Ca signaling, and cell death. The uniporter contains the pore-forming MCU subunit, the auxiliary EMRE protein, and the regulatory MICU1 subunit, which blocks the MCU pore under resting cellular Ca concentrations.
View Article and Find Full Text PDFTrends Pharmacol Sci
November 2024
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA. Electronic address:
Regulation of mitochondrial calcium uptake by the mitochondrial calcium uniporter (mtCU) complex is crucial for heart function. In a recent study, Hasan et al. demonstrated that mitochondrial calcium uptake (MICU)1 and MICU2, regulatory subunits of the complex, help maintain calcium homeostasis in cardiac mitochondria, providing potential targets for therapies aimed at improving mitochondrial function in heart disease.
View Article and Find Full Text PDFEMBO J
November 2024
Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum Munich, Munich, Germany.
The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
August 2024
Department of Pathology and Genomic Medicine, MitoCare Center, Thomas Jefferson University, Philadelphia, PA 19107.
Activating Ca-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU.
View Article and Find Full Text PDFJ Physiol
July 2024
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
Increased malignancy and poor treatability associated with solid tumour cancers have commonly been attributed to mitochondrial calcium (Ca) dysregulation. The mitochondrial Ca uniporter complex (mtCU) is the predominant mode of Ca uptake into the mitochondrial matrix. The main components of mtCU are the pore-forming mitochondrial Ca uniporter (MCU) subunit, MCU dominant-negative beta (MCUb) subunit, essential MCU regulator (EMRE) and the gatekeeping mitochondrial Ca uptake 1 and 2 (MICU1 and MICU2) proteins.
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