MICU1 regulates mitochondrial cristae structure and function independent of the mitochondrial calcium uniporter channel

Abstract

1MICU1 is an EF-hand-containing mitochondrial protein that is essential for gating of the 2 mitochondrial Ca 2+ uniporter channel (mtCU) and is reported to interact directly with the pore-3 forming subunit, MCU and scaffold EMRE. However, using size-exclusion proteomics, we found 4

The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporter

“…One of the controversial elements in previously published experiments is the explanation of the cause of the ‘threshold’ of the MCU cx Ca 2+ influx into the matrix ( Csordás et al, 2013 ; Tomar et al, 2019 ; Foskett and Madesh, 2014 ; Hoffman et al, 2013 ; Mallilankaraman et al, 2012b ; Perocchi et al, 2010 ; Tufi et al, 2019 ). It was noted initially ( Mallilankaraman et al, 2012b ) that there is a cytosolic concentration of Ca 2+ ([Ca 2+ ] i ) below which there is no MCU cx -medicated Ca 2+ influx.…”

“…Additional recent modifications of this hypothesis add the prediction that allosteric actions of MICU1 on MCU cx account for any inconsistencies or contradictions of the plug hypothesis ( Csordás et al, 2013 ). Moreover, new findings suggest that there may be broad actions of MICU1 on non-MCU cx targets within the mitochondria ( Tomar et al, 2019 ; Gottschalk et al, 2019 ; Tufi et al, 2019 ). These findings and the unrefined and untested modifications of the plug hypothesis motivate additional investigations.…”

“…From the IMS, Ca 2+ crosses the nearly impermeant inner mitochondrial membrane (IMM) in a highly regulated manner into the mitochondrial matrix through the small conductance, highly selective MCU cx ( Kirichok et al, 2004 ; Williams et al, 2013 ). The recent dynamic and exciting body of work investigating Ca 2+ movement through the MCU cx has led to a number of controversial and perplexing reports ( Csordás et al, 2013 ; Tomar et al, 2019 ; Foskett and Madesh, 2014 ; Gottschalk et al, 2019 ; Hoffman et al, 2013 ; Mallilankaraman et al, 2012b ; Nemani et al, 2018 ; Perocchi et al, 2010 ; Tufi et al, 2019 ; Supplementary file 1a and b ). These publications also provoke the possibility that the molecular components of MCU cx have additional broad actions in mitochondria which could complicate our understanding ( Tomar et al, 2019 ; Gottschalk et al, 2019 ; Tufi et al, 2019 ).…”

“…The recent dynamic and exciting body of work investigating Ca 2+ movement through the MCU cx has led to a number of controversial and perplexing reports ( Csordás et al, 2013 ; Tomar et al, 2019 ; Foskett and Madesh, 2014 ; Gottschalk et al, 2019 ; Hoffman et al, 2013 ; Mallilankaraman et al, 2012b ; Nemani et al, 2018 ; Perocchi et al, 2010 ; Tufi et al, 2019 ; Supplementary file 1a and b ). These publications also provoke the possibility that the molecular components of MCU cx have additional broad actions in mitochondria which could complicate our understanding ( Tomar et al, 2019 ; Gottschalk et al, 2019 ; Tufi et al, 2019 ). Here, we use an array of quantitative tools to directly examine the conductance of the MCU cx channel and how it is gated by MICU subunits.…”

The mitochondrial Ca 2+ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis

“…These hypotheses may be supported by some reports indicating that MCU‐knockout mice are viable (Pan et al, 2013), and that MCU‐independent Ca 2+ uptake is also induced by ryanodine receptors, TRPC3, UCP2/3, and LETM1 (Trenker et al, 2007; Jiang et al, 2009; Ryu et al, 2010; Feng et al, 2013). Moreover, MICU1 controls cristae structure in a MCU‐independent manner (Gottschalk et al, 2019; Tomar et al , 2019). Thus, the cell death mediated by MICU1/MCU double deficiency might be caused by the mitochondrial Ca 2+ regulation in a MCU complex‐independent manner.…”