The Molecular Mechanisms of Mitochondrial Calcium Uptake by Calcium Uniporter

Abstract

Mitochondria play a role as intracellular calcium stores as well as energy conversion functions. Excessive calcium accumulation in mitochondria induces cell death and induces diseases such as ischemia-reperfusion injury. Mitochondrial calcium uptake is considered to be mediated by calcium uniporters, which have attracted much attention as potential drug targets. Although calcium uniporter was shown to function as an ion channel, the molecular mechanisms have long been unclear. In this decade, the molecular composition of the calcium uniporter complex was discovered; the calcium uniporter consists of the 7 subunits. Each subunit has no structural similarity to other Ca ion channels; thus, the novel molecular mechanism of the Ca 2＋ uptake by calcium uniporter is of interest. Although calcium uniporter is conserved in human to warm, yeast lack mitochondrial calcium uptake activity. In the previous study, various subunits of mammalian calcium uniporter were expressed in the yeast mitochondria. As a result, although the expression of each subunit alone did not aŠect on the mitochondrial calcium uptake activity, the co-expression of mitochondrial calcium uniporter (MCU) and essential MCU regulator (EMRE) enabled to reconstitute calcium uptake activity in yeast mitochondria. This indicated that MCU and EMRE are key factors of the calcium uptake activity in mitochondria. This yeast reconstitution technique has also enabled us to perform detailed structure-function analysis of the MCU and EMRE. In this paper, we will discuss the molecular mechanism of Ca 2＋ uptake and the prospects for drug discovery.

Regulatory mechanisms of mitochondrial calcium uptake by the calcium uniporter complex

“…Previous studies reported that the MCU interacts with the regulatory subunits MCUR1 and EMRE [13,14]. However, our analysis showed that MCUR1 and EMRE are irrelevant to the functional importance of either domain, indicating that CC1 and CC2 of the MCU do not form a coiled-coil structure with the regulatory subunits, but rather between CC1 and CC2, which is important for channel pore formation in the MCU [25,26].…”

The Regulatory Roles of Mitochondrial Calcium and the Mitochondrial Calcium Uniporter in Tumor Cells

“…[ 36 ]. In fact, the uptake and release of Ca 2+ by mitochondria can be regulated by the one-way transport mechanism or transporter [ 37 ]. The mitochondrial Ca 2+ influx is mainly mediated by the mitochondrial calcium uniporter (MCU), voltage-dependent anion-selective channel (VDAC), and mitochondrial ryanodine receptor transporter.…”