Liron Boyman and W. Jonathan Lederer; PNAS September 15, 2020 117 (37) 22634-22636

Figure: Ca²⁺ flux through MCU_cx. 

Cytosolic calcium enters the mitochondrial matrix through the mitochondrial calcium uniporter (MCU) where it acts as a signal that regulates ATP production (1), metabolic fuel selection (1⇓–3), and if excessively high, triggers cell death (4). The complete complex of the MCU subunits is now referred to as the mitochondrial calcium uniporter holocomplex (MCU_cx) (5). In PNAS, Vais et al. (6) focus on how the levels of Ca²⁺ inside the mitochondrial matrix ([Ca²⁺]_m) can regulate the MCU_cx itself. Here, the MCU_cx was investigated by patch clamping a vesicular preparation made from the inner mitochondrial membrane (IMM) of a single mitochondrion, called a “mitoplast” (Fig. 1A). This approach was pioneered 17 y ago by Yuriy Kirichok, Grigory Krapivinsky, and David Clapham (7) and was a huge step toward our understanding of how mitochondria work. By patch clamping single mitoplasts from COS-7 cells or a region of the mitoplast membrane, they identified a femto-Siemens (fS) single-channel conductance under physiological conditions. It was highly selective for Ca²⁺ and had an open probability (P_o) that was steeply voltage dependent. They suggested that this channel was a good candidate for the MCU_cx (Fig. 1B). Two independent groups (8, 9) then showed that a molecular component of MCU_cx was the likely pore-forming subunit, here called MCU_pore but also frequently called “the MCU.” Elucidation of MCU_cx structure and function also included the identification of key auxiliary subunits including MICU1-3 (mitochondrial calcium uptake 1-3) and EMRE (essential MCU regulator) (10, 11). Hugely important to our broad understanding of MCU_cx was the follow-up work by the Kirichok laboratory. They suggested that there were critical differences in the multisubunit MCU_cx in different tissues (12). For example, mitoplasts from different tissues had dramatically different MCU_cx current densities! Mouse heart mitoplasts had a significantly lower I_MCUcx density than did mitoplasts from skeletal muscle, liver, kidney, and brown fat in mouse. Drosophila flight muscle mitoplasts had barely detectable I_MCUcx compared with all other types of mitoplasts. Furthermore, Williams et al. (13) showed that another specific tissue-dependent feature of I_MCUcx density was that it appears to decrease as mitochondrial volume fraction within different types of cells increased. Thus, in heart muscle cells and in Drosophila flight muscle cells where mitochondria are more abundant than in any other cell type, the I_MCUcx density was the lowest. These observations and others (14⇓–16) all suggest that the regulation of the MCU_cx and its function depends importantly on the tissues and organisms in which the mitochondria are located.

See https://www.pnas.org/content/117/37/22634