Molecular regulation of MCU: Implications in physiology and disease

Abstract

Ca²⁺ flux across the inner mitochondrial membrane (IMM) regulates cellular bioenergetics, intra-cellular cytoplasmic Ca²⁺ signals, and various cell death pathways. Ca²⁺ entry into the mitochondria occurs due to the highly negative membrane potential (ΔΨ_m) through a selective inward rectifying MCU channel. In addition to being regulated by various mitochondrial matrix resident proteins such as MICUs, MCUb, MCUR1 and EMRE, the channel is transcriptionally regulated by upstream Ca²⁺ cascade, post transnational modification and by divalent cations. The mode of regulation either inhibits or enhances MCU channel activity and thus regulates mitochondrial metabolism and cell fate.

Keywords: Calcium; Channel; EMRE; MCU; MCUR1; MCUb; MICU1; Magnesium; MiST; Miro1; Mitochondria; Oxidants; SLC25A23.

Figure 1

MCU super complex in physiology and pathology. Ca²⁺ enters the mitochondria through MCU channel. MCU, the pore-forming subunit is a pentamer with N and C terminal domains in the matrix. MCUR1 and EMRE are transmembrane proteins that interact with MCU and regulate _mCa²⁺ uptake by the channel. Under conditions of oxidative stress, C97 at the NTD of MCU gets S-glutathionylated promoting MCU oligomerization and increasing _mCa²⁺ uptake leading to Ca²⁺ overload and swelling of the mitochondria.

Figure 2

Loss of MCU elicits elevated [Ca²⁺]_c – induced MiST. Actively respiring filamentous mitochondria that are tethered to microtubules through interactions of Miro and kinesin, take up _cCa²⁺ in response to agonist stimulation through the MCU channel for bioenergetic output. Loss of _mCa²⁺ uptake in the absence of MCU causes elevated _cCa²⁺. Sustained elevated _cCa²⁺ binds the EF hand of Mior1 and releases the mitochondria from microtubules thus causing a change in mitochondrial shape.