Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter
نویسندگان
چکیده
The mitochondrial calcium uniporter (MCU) is responsible for mitochondrial calcium uptake and homeostasis. It is also a target for the regulation of cellular anti-/pro-apoptosis and necrosis by several oncogenes and tumour suppressors. Herein, we report the crystal structure of the MCU N-terminal domain (NTD) at a resolution of 1.50 Å in a novel fold and the S92A MCU mutant at 2.75 Å resolution; the residue S92 is a predicted CaMKII phosphorylation site. The assembly of the mitochondrial calcium uniporter complex (uniplex) and the interaction with the MCU regulators such as the mitochondrial calcium uptake-1 and mitochondrial calcium uptake-2 proteins (MICU1 and MICU2) are not affected by the deletion of MCU NTD. However, the expression of the S92A mutant or a NTD deletion mutant failed to restore mitochondrial Ca(2+) uptake in a stable MCU knockdown HeLa cell line and exerted dominant-negative effects in the wild-type MCU-expressing cell line. These results suggest that the NTD of MCU is essential for the modulation of MCU function, although it does not affect the uniplex formation.
منابع مشابه
The Effects of EGTA on the Quality of Fresh and Cryopreserved-Thawed Human Spermatozoa
Background: Sperm cryopreservation-thawing process has damaging effects on the structure and function of sperm, namely cryoinjury. Calcium overload has been reported as a postulated mechanism for sperm damage during the first steps after thawing. This study was designed to assess the intracellular calcium (Ca2+i) after cryopreservation and to clarify the role of a calcium chelator ethylene glyc...
متن کاملO-9: The Central Role of Mitochondrial Function in Quality of Human Oocyte
Background: Mitochondria are the most aboudent and small essential organelles found in eukaryotic cells. These are semiautonomous organelles for the production of cellular ATP that through its various biochemical pathways. The primary pathway for ATP production is OXPHOS via the electron transfer chain (ETC) which is encoded by nuclear DNA and mtdna genomes. Mitochondria consist of double stran...
متن کاملDual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex
Mitochondrial Ca(2+) uptake, a process crucial for bioenergetics and Ca(2+) signaling, is catalyzed by the mitochondrial calcium uniporter. The uniporter is a multi-subunit Ca(2+)-activated Ca(2+) channel, with the Ca(2+) pore formed by the MCU protein and Ca(2+)-dependent activation mediated by MICU subunits. Recently, a mitochondrial inner membrane protein EMRE was identified as a uniporter s...
متن کاملFunction of mitochondrial complex-I and -IV in normal human and Parkinson's disease cybrids
Mitochondrial dysfunction has been implicated in the dopaminergic neurodegeneration, which characterizes Parkinson’s disease (PD). The activities of mitochondrial complexes I and IV were found to be reduced in the brains of PD patients (n = 4) as compared to age-matched controls (n = 4). This is tested in SH-SY5Y cell lines, transformed Rho0 cells, and in normal and PD cybrid cell lines. Cybrid...
متن کاملFunction of mitochondrial complex-I and -IV in normal human and Parkinson's disease cybrids
Mitochondrial dysfunction has been implicated in the dopaminergic neurodegeneration, which characterizes Parkinson’s disease (PD). The activities of mitochondrial complexes I and IV were found to be reduced in the brains of PD patients (n = 4) as compared to age-matched controls (n = 4). This is tested in SH-SY5Y cell lines, transformed Rho0 cells, and in normal and PD cybrid cell lines. Cybrid...
متن کامل