Abstract
The mitochondrial calcium uniporter (MCU) is a calcium-activated calcium channel critical for signaling and bioenergetics. MCU, the pore-forming subunit of the uniporter, contains two transmembrane domains and is found in all major eukaryotic taxa. In amoeba and fungi, MCU homologs are sufficient to form a functional calcium channel, whereas human MCU exhibits a strict requirement for the metazoan protein essential MCU regulator (EMRE) for conductance. Here, we exploit this evolutionary divergence to decipher the molecular basis of human MCU's dependence on EMRE. By systematically generating chimeric proteins that consist of EMRE-independent Dictyostelium discoideum MCU and Homo sapiens MCU (HsMCU), we converged on a stretch of 10 amino acids in D. discoideum MCU that can be transplanted to HsMCU to render it EMRE independent. We call this region in human MCU the EMRE dependence domain (EDD). Crosslinking experiments show that EMRE directly interacts with HsMCU at its transmembrane domains as well as the EDD. Our results suggest that EMRE stabilizes the EDD of MCU, permitting both channel opening and calcium conductance, consistent with recently published structures of MCU-EMRE.
Highlights
Mitochondria play central roles in diverse cellular processes including metabolism, signaling, and cell death
essential MCU regulator (EMRE) has emerged as a core component of the animal mitochondrial Ca2+ uniporters whose expression is under transcriptional and posttranslational control (Konig et al, 2016; Munch & Harper, 2016; Tsai et al, 2017)
In a mouse model of neuromuscular disease caused by MICU1 deficiency, decreased EMRE expression over time correlated with improved health (Liu et al, 2016)
Summary
Mitochondria play central roles in diverse cellular processes including metabolism, signaling, and cell death. Calcium (Ca2+) signaling is critical for coordination of cellular needs with mitochondrial outputs by regulating the activity of the tricarboxylic acid cycle, activity of mitochondrial metabolite carriers, and triggering the mitochondrial permeability transition pore (Denton, 2009; Del Arco et al, 2016; Giorgio et al, 2018). This coordination is partially mediated by entry of Ca2+ into the mitochondrial matrix from the cytosol during a Ca2+ signaling event. MCUb is a paralog of MCU and is thought to be a negative regulator of MCU because of its inability to form a functional Ca2+ channel (Raffaello et al, 2013)
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