bims-cytox1 2019-11-03 papers

Issue of 2019–11–03
six papers selected by
Gavin McStay, Staffordshire University

Biochem Soc Trans. 2019 Oct 31. pii: BST20190153. [Epub ahead of print]

Multifaceted roles of porin in mitochondrial protein and lipid transport.

Mitochondria are essential eukaryotic organelles responsible for primary cellular energy production. Biogenesis, maintenance, and functions of mitochondria require correct assembly of resident proteins and lipids, which require their transport into and within mitochondria. Mitochondrial normal functions also require an exchange of small metabolites between the cytosol and mitochondria, which is primarily mediated by a metabolite channel of the outer membrane (OM) called porin or voltage-dependent anion channel. Here, we describe recently revealed novel roles of porin in the mitochondrial protein and lipid transport. First, porin regulates the formation of the mitochondrial protein import gate in the OM, the translocase of the outer membrane (TOM) complex, and its dynamic exchange between the major form of a trimer and the minor form of a dimer. The TOM complex dimer lacks a core subunit Tom22 and mediates the import of a subset of mitochondrial proteins while the TOM complex trimer facilitates the import of most other mitochondrial proteins. Second, porin interacts with both a translocating inner membrane (IM) protein like a carrier protein accumulated at the small TIM chaperones in the intermembrane space and the TIM22 complex, a downstream translocator in the IM for the carrier protein import. Porin thereby facilitates the efficient transfer of carrier proteins to the IM during their import. Third, porin facilitates the transfer of lipids between the OM and IM and promotes a back-up pathway for the cardiolipin synthesis in mitochondria. Thus, porin has roles more than the metabolite transport in the protein and lipid transport into and within mitochondria, which is likely conserved from yeast to human.

Keywords: VDAC; mitochondria; phospholipid transport; porin; protein import; translocator

DOI: https://doi.org/10.1042/BST20190153

Mitochondrion. 2019 Oct 25. pii: S1567-7249(19)30139-4. [Epub ahead of print]

Modular Biogenesis of Mitochondrial Respiratory Complexes.

Mario H Barros, Gavin P McStay.

Mitochondrial function relies on the function of oxidative phosphorylation to synthesise ATP and generate an electrochemical gradient across the inner mitochondrial membrane. These coupled processes are mediated by five multi-subunit complexes that reside in this inner membrane. These complexes are the product of both nuclear and mitochondrial gene products. Defects in the function or assembly of these complexes can lead to mitochondrial diseases due to deficits in energy production and mitochondrial functions. Appropriate biogenesis and function are mediated by a complex number of assembly factors that promote maturation of specific complex subunits to form the active oxidative phosphorylation complex. The understanding of the biogenesis of each complex has been informed by studies in both simple eukaryotes such as Saccharomyces cerevisiae and human patients with mitochondrial diseases. These studies reveal each complex assembles through a pathway using specific subunits and assembly factors to form kinetically distinct but related assembly modules. The current understanding of these complexes has embraced the revolutions in genomics and proteomics to further our knowledge on the impact of mitochondrial biology in genetics, medicine, and evolution.

DOI: https://doi.org/10.1016/j.mito.2019.10.008

Mol Cell. 2019 Oct 18. pii: S1097-2765(19)30732-4. [Epub ahead of print]

The NADH Dehydrogenase Nde1 Executes Cell Death after Integrating Signals from Metabolism and Proteostasis on the Mitochondrial Surface.

SreeDivya Saladi, Felix Boos, Michael Poglitsch, Hadar Meyer, Frederik Sommer, Timo Mühlhaus, Michael Schroda, Maya Schuldiner, Frank Madeo, Johannes M Herrmann.

The proteolytic turnover of mitochondrial proteins is poorly understood. Here, we used a combination of dynamic isotope labeling and mass spectrometry to gain a global overview of mitochondrial protein turnover in yeast cells. Intriguingly, we found an exceptionally high turnover of the NADH dehydrogenase, Nde1. This homolog of the mammalian apoptosis inducing factor, AIF, forms two distinct topomers in mitochondria, one residing in the intermembrane space while the other spans the outer membrane and is exposed to the cytosol. The surface-exposed topomer triggers cell death in response to pro-apoptotic stimuli. The surface-exposed topomer is degraded by the cytosolic proteasome/Cdc48 system and the mitochondrial protease Yme1; however, it is strongly enriched in respiratory-deficient cells. Our data suggest that in addition to their role in electron transfer, mitochondrial NADH dehydrogenases such as Nde1 or AIF integrate signals from energy metabolism and cytosolic proteostasis to eliminate compromised cells from growing populations.

Keywords: NADH:ubiquinone dehydrogenase; apoptosis; apoptosis-inducing factor; mitochondria; protein import; respiration

DOI: https://doi.org/10.1016/j.molcel.2019.09.027

Biochim Biophys Acta Bioenerg. 2019 Oct 26. pii: S0005-2728(19)30138-0. [Epub ahead of print] 148091

The spatio-temporal organization of mitochondrial F1FO ATP synthase in cristae depends on its activity mode.

Kirill Salewskij, Bettina Rieger, Frances Hager, Tasnim Arroum, Patrick Duwe, Jimmy Villalta, Sara Colgiati, Christian P Richter, Olympia E Psathaki, José A Enriquez, Timo Dellmann, Karin B Busch.

F1FO ATP synthase is a key enzyme of mitochondrial energy metabolism which works in two directions. It is not known whether ATP synthase and ATPase function are correlated with different spatio-temporal organization of the enzyme. To analyze this, we have tracked and localized individual ATP synthase/ATPase molecules in situ by live cell microscopy. Under normal conditions, ATP synthase is restricted mainly to cristae. A mobile fraction exist that displays orthogonal trajectories following the cristae membranes but also move in the IBM. By inhibiting glycolysis, we induced ATP hydrolysis in addition to ATP synthesis. The coexistence of two subpopulations was supported by data from single molecule localization and tracking analysis. We found that the spatial-temporal organization of ATP synthase was flexible and mirrored the physiological data. The clear cristae-related structuring of the ATP synthase/ATPase was obliterated when glycolysis was inhibited. At the same time, ATP synthase dimers decreased. The ratiometric change in dimeric/monomeric, respectively more mobile/less mobile ATP synthase was reversible. In IF1-KO cells, ATP synthase was more mobile, while inhibition of ATPase activity decreased the mobility. Together this data strongly supports the model of distinct subpopulations of ATP synthase and ATP hydrolase, the latter with higher mobility and likely present in the IBM compartment. Obviously, ATP synthase reacts quickly and reversibly to metabolic conditions, not only through functional but also through spatial and structural re-organization.

Keywords: ATP synthase dimers; F(1)F(O) ATP synthase; Metabolic adaptation; Mitochondria; OXPHOS; Reverse ATP synthase activity; Spatio-temporal organization; Superresolution microscopy; Tracking and localization microscopy (TALM); Ultrastructure

DOI: https://doi.org/10.1016/j.bbabio.2019.148091

Mitochondrion. 2019 Oct 26. pii: S1567-7249(19)30149-7. [Epub ahead of print]

The basic machineries for mitochondrial protein quality control.

Carmela Vazquez-Calvo, Tamara Suhm, Sabrina Büttner, Martin Ott.

Mitochondria play pivotal roles in cellular energy metabolism, the synthesis of essential biomolecules and the regulation of cell death and aging. The proper folding, unfolding and degradation of the many proteins active within mitochondria is surveyed by the mitochondrial quality control machineries. Here, we describe the principal components of the mitochondrial quality control system and recent developments in the elucidation of the molecular mechanisms maintaining a functional mitochondrial proteome.

Keywords: Aggregates; Chaperones; Mitochondria; Mitophagy; Proteases; Proteostasis; Quality control

DOI: https://doi.org/10.1016/j.mito.2019.10.003

Mol Cell Proteomics. 2019 Oct 30. pii: mcp.RA119.001784. [Epub ahead of print]

The mitochondrial acyl-carrier protein interaction network highlights important roles for LYRM family members in complex I and mitoribosome assembly.

Marris G Dibley, Luke E Formosa, Baobei Lyu, Boris Reljic, Dylan McGann, Linden Muellner-Wong, Felix Kraus, Alice J Sharpe, David A Stroud, Michael T Ryan.

NDUFAB1 is the mitochondrial acyl carrier protein (ACP) essential for cell viability. Through its pantetheine-4'-phosphate post-translational modification, NDUFAB1 interacts with members of the leucine-tyrosine-arginine motif (LYRM) protein family. Although a number of LYRM proteins have been described to participate in a variety of defined processes, the functions of others remain either partially or entirely unknown. We profiled the interaction network of NDUFAB1 to reveal associations with 9 known LYRM proteins as well as more than 20 other proteins involved in mitochondrial respiratory chain complex and mitochondrial ribosome assembly. Subsequent knockout and interaction network studies in human cells revealed the LYRM member AltMiD51 to be important for optimal assembly of the large mitoribosome subunit, consistent with recent structural studies. In addition, we used proteomics coupled with topographical heat-mapping to reveal that knockout of LYRM2 impairs assembly of the NADH-dehydrogenase module of complex I, leading to defects in cellular respiration. Together, this work adds to the catalogue of functions executed by LYRM family of proteins in building mitochondrial complexes and emphasises the common and essential role of NDUFAB1 as a protagonist in mitochondrial metabolism.

Keywords: Acyl-Carrier Protein; Affinity proteomics; Blue Native Polyacrylamide Gel Electrophoresis; Complex I; Mitochondria function or biology; Protein complex analysis; Protein structure*; Protein-Protein Interactions*

DOI: https://doi.org/10.1074/mcp.RA119.001784