Mitochondrial Outer Membrane Channels: Emerging Diversity in Transport Processes

Becker, Thomas; Wagner, Richard

doi:10.1002/bies.201800013

Cited by 48 publications

(28 citation statements)

References 105 publications

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“…Human mitochondria contain more than a thousand proteins that exert its diverse functions (Calvo et al, 2016). The vast majority of these proteins are encoded in the nuclear genome, translated in the cytoplasm and imported into mitochondria (Schmidt et al, 2010;Becker and Wagner, 2018). Almost all proteins are inserted through the translocase of the outer membrane (TOM complex) (Kang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Factors Involved in Localized Translation Near Mitochondria by Ribosome-Proximity Labeling

Vardi-Oknin

Arava

2019

Front. Cell Dev. Biol.

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Mitochondria exert their many functions through a repertoire of hundreds of proteins. The vast majority of these proteins are encoded in the nuclear genome, translated in the cytosol and imported into the mitochondria. Current models, derived mainly from work in yeast, suggest that the translation of many of these proteins can occur in close vicinity to the mitochondria outer membrane by localized ribosomes. Here, we applied ribosomeproximity biotin labeling to address this possibility. A clear biotinylation of ribosomes by mitochondrial Tom20-BirA fusion protein was observed in a human cell line. Isolation of these ribosomes revealed their preferred association with mRNAs encoding mitochondrial proteins. Furthermore, knock down of the mitochondrial protein receptor Tom70 resulted in a decrease in ribosomes translating mRNAs encoding proteins predicted to be recognized by Tom70. Intriguingly, levels of ribosomes translating mRNAs encoding targets of Tom20 were increased. We also knocked down the RNA binding protein CLUH that is implicated in regulation of mRNA encoding mitochondrial proteins, and found an increase in association of CLUH targets with mitochondriaproximal ribosomes. This is consistent with a role for CLUH in maintaining mRNAs encoding mitochondrial proteins in the cytosol. Overall, these data shed light on factors that contribute to association of translating ribosomes with human mitochondria and may suggest a co-translational mode of protein import into this organelle.

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Section: Introductionmentioning

confidence: 99%

Characterization of Factors Involved in Localized Translation Near Mitochondria by Ribosome-Proximity Labeling

Vardi-Oknin

Arava

2019

Front. Cell Dev. Biol.

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“…CICs are indanyloxyacetic acid‐94 (IAA‐94)‐sensitive, but several mitochondrial CIC family members are present also in the endoplasmic reticulum (Ponnalagu et al ., ) making it difficult to delineate the function of mitochondrial CICs by pharmacological means. The existence of CICs and K ir channels, both small‐conductance channels, in the OMM challenges the traditional view that the outer membrane forms an unspecific size‐exclusion filter for the flux of small hydrophilic molecules (Becker and Wagner, ). In yeast mitochondria, the recent identification of three novel ion channels in the OMM with unknown substrate specificity (Kruger et al ., ) points to the same conclusion (Checchetto and Szabo, ).…”

Section: Mitochondrial Outer Membrane (Omm) Channelsmentioning

confidence: 96%

Pharmacological modulation of mitochondrial ion channels

Leanza

Checchetto

Biasutto

et al. 2019

British J Pharmacology

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The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner membranes. Relevant information about the function of these channels in physiological and pathological settings was gained thanks to genetic models for a few, mitochondria‐specific channels. However, many ion channels have multiple localizations within the cell, hampering a clear‐cut determination of their function by pharmacological means. The present review summarizes our current knowledge about the ins and outs of mitochondrial ion channels, with special focus on the channels that have received much attention in recent years, namely, the voltage‐dependent anion channels, the permeability transition pore (also called mitochondrial megachannel), the mitochondrial calcium uniporter and some of the inner membrane‐located potassium channels. In addition, possible strategies to overcome the difficulties of specifically targeting mitochondrial channels versus their counterparts active in other membranes are discussed, as well as the possibilities of modulating channel function by small peptides that compete for binding with protein interacting partners. Altogether, these promising tools along with large‐scale chemical screenings set up to identify new, specific channel modulators will hopefully allow us to pinpoint the actual function of most mitochondrial ion channels in the near future and to pharmacologically affect important pathologies in which they are involved, such as neurodegeneration, ischaemic damage and cancer. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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“…This membrane is highly permeable to cations, anions, and molecules with molecular weights < 5 kDa due to the presence of large conductance channels. These channels, formed by voltage-dependent anion channel proteins (VDACs), allow for the exchange of Ca 2+ and small molecules by concentration gradients [ 2 , 43 , 44 , 45 , 46 , 47 ]. They not only regulate transport of Ca 2+ from the cytoplasm into the intermembrane space (IMS), but are additionally engaged in the mediation of cellular metabolism by transporting ATP and other small metabolites across the OMM [ 12 , 48 ].…”

Section: Calcium Transport Systems In Mitochondriamentioning

confidence: 99%

Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins

Naumova

Šachl

2020

Membranes

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Mitochondria represent the fundamental system for cellular energy metabolism, by not only supplying energy in the form of ATP, but also by affecting physiology and cell death via the regulation of calcium homeostasis and the activity of Bcl-2 proteins. A lot of research has recently been devoted to understanding the interplay between Bcl-2 proteins, the regulation of these interactions within the cell, and how these interactions lead to the changes in calcium homeostasis. However, the role of Bcl-2 proteins in the mediation of mitochondrial calcium homeostasis, and therefore the induction of cell death pathways, remain underestimated and are still not well understood. In this review, we first summarize our knowledge about calcium transport systems in mitochondria, which, when miss-regulated, can induce necrosis. We continue by reviewing and analyzing the functions of Bcl-2 proteins in apoptosis. Finally, we link these two regulatory mechanisms together, exploring the interactions between the mitochondrial Ca2+ transport systems and Bcl-2 proteins, both capable of inducing cell death, with the potential to determine the cell death pathway—either the apoptotic or the necrotic one.

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Mitochondrial Outer Membrane Channels: Emerging Diversity in Transport Processes

Cited by 48 publications

References 105 publications

Characterization of Factors Involved in Localized Translation Near Mitochondria by Ribosome-Proximity Labeling

Characterization of Factors Involved in Localized Translation Near Mitochondria by Ribosome-Proximity Labeling

Pharmacological modulation of mitochondrial ion channels

Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins

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