bims-mecmid 2022-05-22 papers

Oncogenesis. 2022 May 19. 11(1): 26

Tumor suppressor p53 restrains cancer cell dissemination by modulating mitochondrial dynamics.

Trinh T T Phan, Yu-Chun Lin, Yu-Ting Chou, Chien-Wei Wu, Lih-Yuan Lin.

Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 expression or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase 9 (MMP9) expression and invasive cell migration. Notably, blocking the activation of mTORC1/MTFP1/Drp1/ERK1/2 axis completely abolishes the p53 deficiency-driven cellular morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized mitochondria-dependent molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.

DOI: https://doi.org/10.1038/s41389-022-00401-x

Commun Biol. 2022 May 17. 5(1): 471

Spatiotemporal stop-and-go dynamics of the mitochondrial TOM core complex correlates with channel activity.

Shuo Wang, Lukas Findeisen, Sebastian Leptihn, Mark I Wallace, Marcel Hörning, Stephan Nussberger.

Single-molecule studies can reveal phenomena that remain hidden in ensemble measurements. Here we show the correlation between lateral protein diffusion and channel activity of the general protein import pore of mitochondria (TOM-CC) in membranes resting on ultrathin hydrogel films. Using electrode-free optical recordings of ion flux, we find that TOM-CC switches reversibly between three states of ion permeability associated with protein diffusion. While freely diffusing TOM-CC molecules are predominantly in a high permeability state, non-mobile molecules are mostly in an intermediate or low permeability state. We explain this behavior by the mechanical binding of the two protruding Tom22 subunits to the hydrogel and a concomitant combinatorial opening and closing of the two β-barrel pores of TOM-CC. TOM-CC could thus represent a β-barrel membrane protein complex to exhibit membrane state-dependent mechanosensitive properties, mediated by its two Tom22 subunits.

DOI: https://doi.org/10.1038/s42003-022-03419-4

Cell Death Differ. 2022 May 18.

Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol.

Louise E King, Ricardo Rodriguez-Enriquez, Robert Pedley, Charlotte E L Mellor, Pengbo Wang, Egor Zindy, Michael R H White, Keith Brennan, Andrew P Gilmore.

Apoptosis is regulated by interactions between the BH3-only and multi-domain Bcl-2 family proteins. These interactions are integrated on the outer mitochondrial membrane (OMM) where they set the threshold for apoptosis, known as mitochondrial priming. However, how mitochondrial priming is controlled at the level of single cells remains unclear. Retrotranslocation of Bcl-XL has been proposed as one mechanism, removing pro-apoptotic Bcl-2 proteins from the OMM, thus reducing priming. Contrary to this view, we now show that Bcl-XL retrotranslocation is inhibited by binding to its BH3-only partners, resulting in accumulation of these protein complexes on mitochondria. We find that Bcl-XL retrotranslocation dynamics are tightly coupled to mitochondrial priming. Quantifying these dynamics indicates the heterogeneity in priming between cells within a population and predicts how they subsequently respond to a pro-apoptotic signal.

DOI: https://doi.org/10.1038/s41418-022-01013-z

Biochim Biophys Acta Bioenerg. 2022 May 14. pii: S0005-2728(22)00038-X. [Epub ahead of print]1863(6): 148569

Beyond being an energy supplier, ATP synthase is a sculptor of mitochondrial cristae.

Héctor Miranda-Astudillo, Marcos Ostolga-Chavarría, Pierre Cardol, Diego González-Halphen.

Mitochondrial F1FO-ATP synthase plays a key role in cellular bioenergetics; this enzyme is present in all eukaryotic linages except in amitochondriate organisms. Despite its ancestral origin, traceable to the alpha proteobacterial endosymbiotic event, the actual structural diversity of these complexes, due to large differences in their polypeptide composition, reflects an important evolutionary divergence between eukaryotic lineages. We discuss the effect of these structural differences on the oligomerization of the complex and the shape of mitochondrial cristae.

Keywords: ATP synthase; F(1)-F(O) ATPase; Lineage-specific subunits; Mitochondrial ATPase

DOI: https://doi.org/10.1016/j.bbabio.2022.148569

Front Mol Biosci. 2022 ;9 871121

Cotranslational Biogenesis of Membrane Proteins in Bacteria.

Evan Mercier, Xiaolin Wang, Lena A K Bögeholz, Wolfgang Wintermeyer, Marina V Rodnina.

Nascent polypeptides emerging from the ribosome during translation are rapidly scanned and processed by ribosome-associated protein biogenesis factors (RPBs). RPBs cleave the N-terminal formyl and methionine groups, assist cotranslational protein folding, and sort the proteins according to their cellular destination. Ribosomes translating inner-membrane proteins are recognized and targeted to the translocon with the help of the signal recognition particle, SRP, and SRP receptor, FtsY. The growing nascent peptide is then inserted into the phospholipid bilayer at the translocon, an inner-membrane protein complex consisting of SecY, SecE, and SecG. Folding of membrane proteins requires that transmembrane helices (TMs) attain their correct topology, the soluble domains are inserted at the correct (cytoplasmic or periplasmic) side of the membrane, and - for polytopic membrane proteins - the TMs find their interaction partner TMs in the phospholipid bilayer. This review describes the recent progress in understanding how growing nascent peptides are processed and how inner-membrane proteins are targeted to the translocon and find their correct orientation at the membrane, with the focus on biophysical approaches revealing the dynamics of the process. We describe how spontaneous fluctuations of the translocon allow diffusion of TMs into the phospholipid bilayer and argue that the ribosome orchestrates cotranslational targeting not only by providing the binding platform for the RPBs or the translocon, but also by helping the nascent chains to find their correct orientation in the membrane. Finally, we present the auxiliary role of YidC as a chaperone for inner-membrane proteins. We show how biophysical approaches provide new insights into the dynamics of membrane protein biogenesis and raise new questions as to how translation modulates protein folding.

Keywords: N-terminal processing; YidC; cotranslational folding; membrane insertion; membrane protein topology; membrane targeting; translocon

DOI: https://doi.org/10.3389/fmolb.2022.871121

Science. 2022 May 20. 376(6595): 794-795

Mitochondrial complex complexification.

Martijn A Huynen, Dei M Elurbe.

Variation in complex composition provides clues about the function of individual subunits.

DOI: https://doi.org/10.1126/science.abq0368

J Lipid Res. 2022 May 12. pii: S0022-2275(22)00060-8. [Epub ahead of print] 100227

The effects of cardiolipin on the structural dynamics of the mitochondrial ADP/ATP carrier in its cytosol-open state.

Qiuzi Yi, Shihao Yao, Boyuan Ma, Xiaohui Cang.

Cardiolipin (CL) has been shown to play a crucial role in regulating the function of proteins in the inner mitochondrial membrane (IMM). As the most abundant protein of the IMM, the ADP/ATP carrier (AAC) has long been the model of choice to study CL-protein interactions, and specifically bound CLs have been identified in a variety of crystal structures of AAC. However, how CL binding affects the structural dynamics of AAC in atomic detail remains largely elusive. Here we compared all-atom molecular dynamics (MD) simulations on bovine AAC1 in lipid bilayers with and without CLs. Our results show that on the current microsecond simulation time scale: 1) CL binding does not significantly affect overall stability of the carrier or structural symmetry at the matrix-gate level; 2) pocket volumes of the carrier and interactions involved in the matrix-gate network become more heterogeneous in parallel simulations with membranes containing CLs; 3) CL binding consistently strengthens backbone hydrogen bonds within helix H2 near the matrix side; and 4) CLs play a consistent stabilizing role on the domain 1-2 interface through binding with the R30:R71:R151 stacking structure and fixing the M2 loop in a defined conformation. CL is necessary for the formation of this stacking structure, and this structure in turn forms a very stable CL binding site. Such a delicate equilibrium suggests the strictly conserved R30:R71:R151stacking structure of AACs could function as a switch under regulation of CLs. Taken together, these results shed new light on the CL-mediated modulation of AAC function.

Keywords: ATP translocases; Cardiolipin; SLC25; arginine stacking; matrix-gate network; mitochondrial ADP; mitochondrial carriers; molecular dynamics simulation; phospholipid; protein-lipid interactions; solute carrier family 25

DOI: https://doi.org/10.1016/j.jlr.2022.100227