scholarly journals Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination

2021 ◽  
Vol 220 (6) ◽  
Author(s):  
Yumiko Oshima ◽  
Etienne Cartier ◽  
Liron Boyman ◽  
Nicolas Verhoeven ◽  
Brian M. Polster ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Outer Membrane ◽  
Mitochondrial Membrane ◽  
Mitochondrial Fission ◽  
Outer Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Translation ◽  
Inner Membrane ◽  
Translation Fidelity ◽  
Mosaic Distribution

Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell (“mosaic distribution”). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high–cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins.

scholarly journals Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

2012 ◽  
Vol 393 (11) ◽  
pp. 1247-1261 ◽  
Author(s):  
Ralf M. Zerbes ◽  
Ida J. van der Klei ◽  
Marten Veenhuis ◽  
Nikolaus Pfanner ◽  
Martin van der Laan ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Membrane ◽  
Protein Complexes ◽  
Boundary Region ◽  
Inner Mitochondrial Membrane ◽  
Inner Membrane ◽  
Mitochondrial Inner Membrane ◽  
Oligomeric Protein ◽  
Enzyme Complexes ◽  
Boundary Membrane

Abstract Mitofilin proteins are crucial organizers of mitochondrial architecture. They are located in the inner mitochondrial membrane and interact with several protein complexes of the outer membrane, thereby generating contact sites between the two membrane systems of mitochondria. Within the inner membrane, mitofilins are part of hetero-oligomeric protein complexes that have been termed the mitochondrial inner membrane organizing system (MINOS). MINOS integrity is required for the maintenance of the characteristic morphology of the inner mitochondrial membrane, with an inner boundary region closely apposed to the outer membrane and cristae membranes, which form large tubular invaginations that protrude into the mitochondrial matrix and harbor the enzyme complexes of the oxidative phosphorylation machinery. MINOS deficiency comes along with a loss of crista junction structures and the detachment of cristae from the inner boundary membrane. MINOS has been conserved in evolution from unicellular eukaryotes to humans, where alterations of MINOS subunits are associated with multiple pathological conditions.

scholarly journals The Mitochondrial TOM Complex Is Required for tBid/Bax-induced Cytochrome c Release

2007 ◽  
Vol 282 (38) ◽  
pp. 27633-27639 ◽  
Author(s):  
Martin Ott ◽  
Erik Norberg ◽  
Katharina M. Walter ◽  
Patrick Schreiner ◽  
Christian Kemper ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cytochrome C ◽  
Outer Membrane ◽  
Recombinant Proteins ◽  
Mitochondrial Membrane ◽  
Mitochondrial Outer Membrane ◽  
Intermembrane Space ◽  
Outer Mitochondrial Membrane ◽  
Cytochrome C Release ◽  
Unknown Mechanism

Cytochrome c release from mitochondria is a key event in apoptosis signaling that is regulated by Bcl-2 family proteins. Cleavage of the BH3-only protein Bid by multiple proteases leads to the formation of truncated Bid (tBid), which, in turn, promotes the oligomerization/insertion of Bax into the mitochondrial outer membrane and the resultant release of proteins residing in the intermembrane space. Bax, a monomeric protein in the cytosol, is targeted by a yet unknown mechanism to the mitochondria. Several hypotheses have been put forward to explain this targeting specificity. Using mitochondria isolated from different mutants of the yeast Saccharomyces cerevisiae and recombinant proteins, we have now investigated components of the mitochondrial outer membrane that might be required for tBid/Bax-induced cytochrome c release. Here, we show that the protein translocase of the outer mitochondrial membrane is required for Bax insertion and cytochrome c release.

scholarly journals Molecular and topological reorganizations in mitochondrial architecture interplay during Bax-mediated steps of apoptosis

2018 ◽  
Author(s):  
Nicholas R. Ader ◽  
Patrick C. Hoffmann ◽  
Iva Ganeva ◽  
Alicia C. Borgeaud ◽  
Chunxin Wang ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Membrane ◽  
Supramolecular Assembly ◽  
Outer Mitochondrial Membrane ◽  
Comprehensive Model ◽  
Structural Elements ◽  
Correlative Microscopy ◽  
Variable Size ◽  
Inner Membrane ◽  
Membrane Components

ABSTRACTDuring apoptosis, Bcl-2 proteins such as Bax and Bak mediate the release of pro-apoptotic proteins from the mitochondria by clustering on the outer mitochondrial membrane and thereby permeabilizing it. However, it remains unclear how outer membrane openings form. Here, we combined different correlative microscopy and electron cryo-tomography approaches to visualize the effects of Bax activity on mitochondria in human cells. Our data show that Bax clusters localize near outer membrane ruptures of highly variable size. Bax clusters contain structural elements suggesting a higher-order organization of their components. Furthermore, unfolding of inner membrane cristae is coupled to changes in the supramolecular assembly of ATP synthases, particularly pronounced at membrane segments exposed to the cytosol by ruptures. Based on our results, we propose a comprehensive model in which molecular reorganizations of the inner membrane and sequestration of outer membrane components into Bax clusters interplay in the formation of outer membrane ruptures.

scholarly journals Light-inducible Deformation of Mitochondria in Live Cells

2020 ◽  
Author(s):  
Yutong Song ◽  
Peiyuan Huang ◽  
Xiaoying Liu ◽  
Bianxiao Cui ◽  
Liting Duan
Keyword(s):  
Outer Membrane ◽  
Molecular Motors ◽  
Optical Method ◽  
Mitochondrial Membrane ◽  
Motor Proteins ◽  
Morphological Changes ◽  
Live Cells ◽  
Mechanical Forces ◽  
Outer Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane

AbstractMitochondria, the powerhouse of the cell, are dynamic organelles that undergo constant morphological changes. Increasing evidence indicates that mitochondria morphologies and functions can be modulated by mechanical cues. However, the mechano-sensing and -responding properties of mitochondria and the correlation between mitochondrial morphologies and functions are unclear due to the lack of methods to precisely exert mechano-stimulation on and deform mitochondria inside live cells. Here we present an optogenetic approach that uses light to induce deformation of mitochondria by recruiting molecular motors to the outer mitochondrial membrane via light-activated protein-protein hetero-dimerization. Mechanical forces generated by motor proteins distort the outer membrane, during which the inner mitochondrial membrane can also be deformed. Moreover, this optical method can achieve subcellular spatial precision and be combined with other optical dimerizers and molecular motors. This method presents a novel mitochondria-specific mechano-stimulator for studying mitochondria mechanobiology and the interplay between mitochondria shapes and functions.

scholarly journals A discrete pathway for the transfer of intermembrane space proteins across the outer membrane of mitochondria

2014 ◽  
Vol 25 (25) ◽  
pp. 3999-4009 ◽  
Author(s):  
Agnieszka Gornicka ◽  
Piotr Bragoszewski ◽  
Piotr Chroscicki ◽  
Lena-Sophie Wenz ◽  
Christian Schulz ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Membrane ◽  
Alternative Pathway ◽  
Intermembrane Space ◽  
Outer Mitochondrial Membrane ◽  
Membrane Translocation ◽  
Tom Complex ◽  
Precursor Proteins ◽  
Core Components

Mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria with the help of protein translocases. For the majority of precursor proteins, the role of the translocase of the outer membrane (TOM) and mechanisms of their transport across the outer mitochondrial membrane are well recognized. However, little is known about the mode of membrane translocation for proteins that are targeted to the intermembrane space via the redox-driven mitochondrial intermembrane space import and assembly (MIA) pathway. On the basis of the results obtained from an in organello competition import assay, we hypothesized that MIA-dependent precursor proteins use an alternative pathway to cross the outer mitochondrial membrane. Here we demonstrate that this alternative pathway involves the protein channel formed by Tom40. We sought a translocation intermediate by expressing tagged versions of MIA-dependent proteins in vivo. We identified a transient interaction between our model substrates and Tom40. Of interest, outer membrane translocation did not directly involve other core components of the TOM complex, including Tom22. Thus MIA-dependent proteins take another route across the outer mitochondrial membrane that involves Tom40 in a form that is different from the canonical TOM complex.

scholarly journals Constriction and Dnm1p Recruitment Are Distinct Processes in Mitochondrial Fission

2003 ◽  
Vol 14 (5) ◽  
pp. 1953-1963 ◽  
Author(s):  
Aster Legesse-Miller ◽  
Ramiro H. Massol ◽  
Tom Kirchhausen
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Fluorescence Imaging ◽  
Hot Spots ◽  
Mitochondrial Membrane ◽  
Mitochondrial Fission ◽  
Three Dimensional ◽  
Time Lapse ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Matrix ◽  
Different Shapes

Mitochondria undergo cycles of fusion and fission crucial for organelle homeostasis. Fission is regulated partially by recruitment of the large GTPase Dnm1p to the outer mitochondrial membrane. Using three-dimensional time-lapse fluorescence imaging of Saccharomyces cerevisiae cells, we found that Dnm1p-EGFP appears and disappears at “hot spots” along mitochondrial tubes. It forms patches that convert rapidly into different shapes regardless of whether mitochondrial fission ensues or not. Moreover, the thickness of the mitochondrial matrix displays frequent temporal fluctuations apparently unrelated to fission or to recruitment of Dnm1p-EGFP. These results suggest that mitochondrial fission requires coordination of at least two distinct processes.

scholarly journals Uptake of protoporphyrin IX by isolated rat liver mitochondria

1980 ◽  
Vol 188 (2) ◽  
pp. 329-335 ◽  
Author(s):  
M E Koller ◽  
I Romslo
Keyword(s):  
Rat Liver ◽  
Mitochondrial Membrane ◽  
Protoporphyrin Ix ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Inner Mitochondrial Membrane ◽  
Erythropoietic Protoporphyria ◽  
Inner Membrane ◽  
Isolated Rat Liver ◽  
Isolated Rat

Rat liver mitochondria accumulate protoporphyrin IX from the suspending medium into the inner membrane in parallel with the magnitude of the transmembrane K+ gradient (K+in/K+out). Only protoporphyrin IX taken up in parallel with the transmembrane K+ gradient is available for haem synthesis. Coproporphyrins (isomers I and III) are not taken up by the mitochondria. The results support the suggestion by Elder & Evans [(1978) Biochem. J. 172, 345-347] that the prophyrin to be taken up by the inner mitochondrial membrane belongs to the protoporphyrin(ogen) IX series. Protoporphyrin IX at concentrations above 15 nmol/mg of protein has detrimental effects on the structural and functional integrity of the mitochondria. The relevance of these effects to the hepatic lesion in erythropoietic protoporphyria is discussed.

Relationships between mitochondrial outer membranes and agranular reticulum in nervous tissue: ultrastructural observations and a new interpretation

1980 ◽  
Vol 46 (1) ◽  
pp. 129-147
Author(s):  
J. Spacek ◽  
A.R. Lieberman
Keyword(s):  
Nervous Tissue ◽  
Mitochondrial Membrane ◽  
Nerve Cells ◽  
Outer Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Thin Sections ◽  
3 Dimensional ◽  
Outer Membranes ◽  
New Interpretation ◽  
In Cells

This study is concerned with extensions of the outer membranes of mitochondria in cells of nervous tissue, and with possible relationships between the extensions and the agranular reticulum. A variety of preparative techniques was applied to a large number of different central nervous tissues (CNS) and peripheral nervous tissues (PNS), using conventional thin sections, thicker sections (100 nm or more) and 3-dimensional reconstructions of serial thin sections. Extensions were commonly observed, particularly from the ends of longitudinally oriented mitochondria in axons and dendrites. Often these had the appearance of, and could be traced into apparent continuity with, adjacent elements of the agranular membrane. In addition to these apical tubular extensions, we also observed and reconstructed short lateral tubular or sac-like extensions and vesicular protrusions of the outer mitochondrial membrane. We discuss and discount the possibility that the extensions are artefacts, consider the structural and biochemical similarities between the outer mitochondrial membrane and agranular reticulum and propose that the outer mitochondrial is part of the agranular reticulum (or a specialized portion of the agranular reticulum). We suggest that the translocation of mitochondria in nerve cells, and probably in other cells as well, involves movement of the inner mitochondrial membrane and the enclosed matrix (mitoplast) within channels of agranular reticulum in continuity, or in transient continuity, with the outer mitochondrial membrane.

Synthesis of the inner mitochondrial membrane and the intercalation of respiratory enzymes during the cell cycle of Chlorella

1976 ◽  
Vol 21 (2) ◽  
pp. 329-340
Author(s):  
B.G. Forde ◽  
B.E. Gunning ◽  
P.C. John
Keyword(s):  
Cell Cycle ◽  
Succinate Dehydrogenase ◽  
Mitochondrial Membrane ◽  
Extended Period ◽  
Outer Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Chlorella Fusca ◽  
Respiratory Enzymes ◽  
Membrane Area ◽  
Enzyme Molecules

The ratio of inner to outer mitochondrial membrane area remains close to 1–8 throughout the cell cycle in synchronized cells of Chlorella fusca var, vacuolata 211-8p. Using estimates of this ratio, together with our previous estimates of mitochondrial surface area, to calculate the absolute area of inner mitochondrial membrane, it is demonstrated that growth of the inner mitochondrial membrane during the cell cycle occupies an extended period and parallels the growth of the whole cell. In contrast, the synthesis of succinate dehydrogenase and cytochrome oxidase is restricted to the last third of the cell cycle. It is concluded that mitochondrial growth involves the intercalation of periodically synthesized respiratory enzymes into membranes made earlier in the cycle, with consequent 5-fold changes in the density of active enzyme molecules in the membrane. These observations are discussed in relation to the control of mitochondiral membrane synthesis, membrane assembly and respiration rate during the cell cycle.

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