The MCU complex in cell death

Penna, Elisa; Espino, Javier; Stefani, Diego De; Meneghesso, Gaudenzio

doi:10.1016/j.ceca.2017.08.008

Cited by 64 publications

(42 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MCU oligomers form a highly selective Ca 2+ pore that is part of a multiprotein complex composed of a large number of regulators, notably the mitochondria Ca 2+ uptake proteins 1,2,3 (MICU 1,2,3) and the essential MCU regulator (EMRE). These regulators allow a fine tuning of the opening of the MCU pore (Mammucari et al 2018;Nemani et al 2018;Penna et al 2018) and modulate the sigmoidal dependence on Ca 2+ of the MCU (Csordás et al 2013;Patron et al 2014). Specific stoichiometries between the MCU and its regulators may be responsible for the observed tissue-specific differences of activities of the uniporter, and explains, for example, the variation in Ca 2+ dynamics observed in mitochondria of heart and liver (Paillard et al 2017;Wacquier et al 2017).…”

Section: Mitochondrial Ca 2+ Transportersmentioning

confidence: 99%

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

Wacquier

Combettes

Dupont

2019

Cold Spring Harb Perspect Biol

View full text Add to dashboard Cite

Intracellular Ca 2+ signals are well organized in all cell types, and trigger a variety of vital physiological processes. The temporal and spatial characteristics of cytosolic Ca 2+ increases are mainly governed by the fluxes of this ion across the membrane of the endoplasmic/sarcoplasmic reticulum and the plasma membrane. However, various Ca 2+ transporters also allow for Ca 2+ exchanges between the cytoplasm and mitochondria. Increases in mitochondrial Ca 2+ stimulate the production of ATP, which allows the cells to cope with the increased energy demand created by the stimulus. Less widely appreciated is the fact that Ca 2+ handling by mitochondria also shapes cytosolic Ca 2+ signals. Indeed, the frequency, amplitude, and duration of cytosolic Ca 2+ increases can be altered by modifying the rates of Ca 2+ transport into, or from, mitochondria. In this review, we focus on the interplay between mitochondria and Ca 2+ signaling, highlighting not only the consequences of cytosolic Ca 2+ changes on mitochondrial Ca 2+ , but also how cytosolic Ca 2+ dynamics is controlled by modifications of the Ca 2+ -handling properties and the metabolism of mitochondria.

show abstract

Section: Mitochondrial Ca 2+ Transportersmentioning

confidence: 99%

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

Wacquier

Combettes

Dupont

2019

Cold Spring Harb Perspect Biol

View full text Add to dashboard Cite

show abstract

“…Likewise, Ca 2+ signalling is integrated in the IMS. The Ca 2+ uniporter (MCU) in the IMM is the central entry gate for Ca 2+ (coming from either the endoplasmic reticulum or outside the cell) (Kamer et al ., ; Penna et al ., ). The central regulatory subunits of MCU are MICU1, MICU2 and MICU3.…”

Section: Functions Of Ims Proteinsmentioning

confidence: 97%

Cysteine residues in mitochondrial intermembrane space proteins: more than just import

Habich

Salscheider

Riemer

2018

British J Pharmacology

View full text Add to dashboard Cite

The intermembrane space (IMS) is a very small mitochondrial sub-compartment with critical relevance for many cellular processes. IMS proteins fulfil important functions in transport of proteins, lipids, metabolites and metal ions, in signalling, in metabolism and in defining the mitochondrial ultrastructure. Our understanding of the IMS proteome has become increasingly refined although we still lack information on the identity and function of many of its proteins. One characteristic of many IMS proteins are conserved cysteines. Different post-translational modifications of these cysteine residues can have critical roles in protein function, localization and/or stability. The close localization to different ROS-producing enzyme systems, a dedicated machinery for oxidative protein folding, and a unique equipment with antioxidative systems, render the careful balancing of the redox and modification states of the cysteine residues, a major challenge in the IMS. In this review, we discuss different functions of human IMS proteins, the involvement of cysteine residues in these functions, the consequences of cysteine modifications and the consequences of cysteine mutations or defects in the machinery for disulfide bond formation in terms of human health.

show abstract

“…Ca2+ transfer between ER and mitochondrial channels is well documented and is facilitated by the formation of physical contacts between the two organelles -the so-called mitochondria-associated ER membranes (MAMs) (Naon and Scorrano, 2014;Thoudam et al, 2016;Vance, 2014). These tight connections allow for direct Ca2+ transit, creating a high Ca2+ concentration in the vicinity of the mitochondrial Ca2+ uniporter MCU located in the inner mitochondrial membrane, essential for Ca2+ transit through this low affinity receptor (Patron et al, 2013;Penna et al, 2018;Raffaello et al, 2012). Likewise, the RyR-MCU-mediated ER-mitochondrial Ca2+ transfer for TNF-mediated necrosis also appears to require direct contact;…”

Section: Interorganellar Contacts Promote Pathogenic Macrophage Necrosismentioning

confidence: 99%

Tumor Necrosis Factor induces pathogenic programmed macrophage necrosis in tuberculosis through a mitochondrial-lysosomal-endoplasmic reticulum circuit

Redmond

Ramakrishnan

2019

Preprint

View full text Add to dashboard Cite

SUMMARY Necrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis releasing mycobacteria into the extracellular environment where they can grow unrestricted. In zebrafish infected with Mycobacterium marinum, a close relative of Mycobacterium tuberculosis, excess Tumor Necrosis Factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here we show that this necrosis pathway is not mitochondrion-intrinsic but rather results from an interorganellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide which ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors. The resultant mitochondrial calcium overload triggers cyclophilin D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-Type calcium channels as specific druggable targets to intercept mitochondrial calcium overload so as to inhibit macrophage necrosis.

show abstract

The MCU complex in cell death

Cited by 64 publications

References 106 publications

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

Cysteine residues in mitochondrial intermembrane space proteins: more than just import

Tumor Necrosis Factor induces pathogenic programmed macrophage necrosis in tuberculosis through a mitochondrial-lysosomal-endoplasmic reticulum circuit

Contact Info

Product

Resources

About