Mitochondrial Cardiolipin Involved in Outer-Membrane Protein Biogenesis: Implications for Barth Syndrome

Gebert, Natalia; Joshi, Amit; Kutik, Stephan; Becker, Thomas; McKenzie, Matthew; Guan, Xue Li; Mooga, Ved P.; Stroud, David A.; Kulkarni, Gnanada; Wenk, Markus R.; Rehling, Peter; Meisinger, Chris; Ryan, Michael; Wiedemann, Nils; Greenberg, Miriam L.; Pfanner, Nikolaus

doi:10.1016/j.cub.2009.10.074

Cited by 206 publications

(183 citation statements)

References 40 publications

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“…Moreover, it is tempting to assume that the function of protein translocases and especially insertases depends on the biophysical properties of the membrane they are embedded in and therefore on the lipid composition of these membranes. Indeed it has been shown, that the assembly of protein import complexes TOM, TIM22 and TIM23 depend on cardiolipin (Kutik et al, 2008;Gebert et al, 2009). Collectively, our observation that deletion of Mdm10 causes alteration in ergosterol content can help to explain part of the phenotypes of the mdm10D mutant.…”

Section: Discussionmentioning

confidence: 66%

Mcp1 and Mcp2, two novel proteins involved in mitochondrial lipid homeostasis

Tan

Özbalci

Brügger

et al. 2013

Journal of Cell Science

114

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SummaryThe yeast mitochondrial outer membrane (MOM) protein Mdm10 is involved in at least three different processes: (1) association of mitochondria with the endoplasmic reticulum and mitochondrial lipid homeostasis (2) membrane assembly of MOM proteins, and (3) inheritance and morphogenesis of mitochondria. To decipher the precise role of Mdm10 in mitochondrial function, we screened for high-copy suppressors of the severe growth defect of the mdm10D mutant. We identified two novel mitochondrial proteins (open reading frames YOR228c and YLR253w) that we named Mdm10 complementing protein (Mcp) 1 and Mcp2. Overexpression of Mcp1 or Mcp2 restores the alterations in morphology and stability of respiratory chain complexes of mitochondria devoid of Mdm10, but the observed defect in assembly of MOM proteins is not rescued. Lipid analysis demonstrates that elevated levels of Mcp1 and Mcp2 restore the alterations in mitochondrial phospholipid and ergosterol homeostasis in cells lacking Mdm10. Collectively, this work identifies two novel proteins that play a role in mitochondrial lipid homeostasis and describes a role of Mdm10 in ergosterol trafficking.

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Section: Discussionmentioning

confidence: 66%

Mcp1 and Mcp2, two novel proteins involved in mitochondrial lipid homeostasis

Tan

Özbalci

Brügger

et al. 2013

Journal of Cell Science

114

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“…In these mitochondria, the membrane potential is strongly reduced, which blocks protein transport via inner membrane protein translocases (57). Import of ␤-barrel proteins into the mitochondrial outer membrane requires the presence of CL, PE and PC (49,50,75). However, the SAM complex is destabilized in mutant mitochondria impaired in PC or CL but not in PE biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

“…In mutants defective in CL or PE synthesis, the biogenesis of outer membrane ␤-barrel proteins is affected (49,50). Whereas CL is also required for the import of proteins with multiple ␣-helical membrane spans into the outer membrane, this import pathway remains largely unaffected in PE-deficient mitochondria (50,51).…”

mentioning

confidence: 99%

“…Furthermore, both phospholipids promote protein transport into the inner membrane and matrix (52)(53)(54)(55)(56)(57). First, binding of preproteins to the TOM complex is disturbed in PE-and CL-deficient mitochondria (49,50). Second, the activity of the respiratory chain complexes, in particular of the cytochrome c oxidase (complex IV), is decreased in mitochondria with reduced PE or CL content (57)(58)(59).…”

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confidence: 99%

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Phosphatidylcholine Affects Inner Membrane Protein Translocases of Mitochondria

Schuler¹,

Bartolomeo

Mårtensson

et al. 2016

Journal of Biological Chemistry

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Two protein translocases transport precursor proteins into or across the inner mitochondrial membrane. The presequence translocase (TIM23 complex) sorts precursor proteins with a cleavable presequence either into the matrix or into the inner membrane. The carrier translocase (TIM22 complex) inserts multispanning proteins into the inner membrane. Both protein import pathways depend on the presence of a membrane potential, which is generated by the activity of the respiratory chain. The non-bilayer-forming phospholipids cardiolipin and phosphatidylethanolamine are required for the activity of the respiratory chain and therefore to maintain the membrane potential for protein import. Depletion of cardiolipin further affects the stability of the TIM23 complex. The role of bilayer-forming phospholipids like phosphatidylcholine (PC) in protein transport into the inner membrane and the matrix is unknown. Here, we report that import of presequence-containing precursors and carrier proteins is impaired in PC-deficient mitochondria. Surprisingly, depletion of PC does not affect stability and activity of respiratory supercomplexes, and the membrane potential is maintained. Instead, the dynamic TIM23 complex is destabilized when the PC levels are reduced, whereas the TIM22 complex remains intact. Our analysis further revealed that initial precursor binding to the TIM23 complex is impaired in PC-deficient mitochondria. We conclude that reduced PC levels differentially affect the TIM22 and TIM23 complexes in mitochondrial protein transport.Mitochondria fulfill essential functions for the survival of the cell like energy conversion to produce ATP, synthesis of amino acids, lipids, and heme, as well as the generation of iron-sulfur clusters. They contain about 1000 proteins in yeast and 1500 proteins in humans (1, 2). More than 99% of the mitochondrial proteins are synthesized as precursors on cytosolic ribosomes. Mitochondria contain a sophisticated system of protein translocases to import precursor proteins (3-9). The translocase of the outer membrane (TOM 3 complex) forms the general entry gate for most precursor proteins. After passage of the TOM channel, distinct protein translocases sort the preproteins into the different subcompartments: the outer and inner membrane as well as the two aqueous compartments, the matrix and intermembrane space.The majority of mitochondrial proteins are sorted into the inner membrane and the matrix. Two inner membrane-bound protein complexes mediate protein import. The presequence translocase (also termed TIM23 complex) transports precursor proteins with a cleavable presequence into the inner membrane and the matrix, whereas the carrier translocase (also termed TIM22 complex) inserts proteins with multiple transmembrane segments into the inner membrane (3-9). The membrane potential across the inner membrane provides the driving force for both protein import pathways and is generated by the activity of the respiratory chain. Presequence-containing preproteins are directly transferred from the ...

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“…While the importance of lipids in mitochondrial protein import is the recently emerging topic of investigation, the current models A. Slomiany, B. L. Slomiany are based on the assumption that all membranes are identical and formed through the incorporation of individual lipids and proteins into existing cellular prototypes [28] [37] [38] [39].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Membranes Restitution Proceeds via Vesicular Import from ER and Cytosol. Counterparts’ Resemblances and Variances in Mitochondria and Golgi Pathways

Slomiany¹,

Slomiany²

2017

ABC

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The processes of mitochondrial restitution are controlled by nuclear genes that encode proteins synthesized in ER and cytosol and delivered as organelleand membrane-specific transport vesicles. The analysis of the transporters recovered from inner mitochondrial space (Mitosol) revealed that the ERsynthesized mitochondria-specific transport vesicles consist of two carriers, one remaining in outer mitochondrial membrane (OMM), and the other that transfers specific membrane segments to the inner mitochondrial membrane (IMM). The ER-assembled and IMM-committed membrane segments, while first integrated into OMM, undergo intra-mitochondrial lipid modification reflected in the synthesis of cardiolipin (CL) and inversion into Mitosol with load of IMM associated cytosolic proteins. Then, the CL-bedecked vesicles are released from OMM to Mitosol and upon contact with IMM fuse with the membrane, and the release of cytosolic cargo ensues. While ER-assembled mitochondria-specific transport vesicles fuse with OMM with the aid of the cytosolic, phosphatidylglycerol (PG)-specific phospholipase A 2 (PLA 2 ), the Mitosol-contained CL-specific PLA guides vesicles fusion with IMM. The described path of translocation of the membrane segments and the cytosol synthesized proteins into the designated mitochondrial compartments sustains growth and identity of OMM, IMM, maintains protein delivery for intramitochondrial lipid and protein modification in Mitosol, and ensures conformity of the cytosolic proteins cargo delivered to matrix.

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Mitochondrial Cardiolipin Involved in Outer-Membrane Protein Biogenesis: Implications for Barth Syndrome

Cited by 206 publications

References 40 publications

Mcp1 and Mcp2, two novel proteins involved in mitochondrial lipid homeostasis

Mcp1 and Mcp2, two novel proteins involved in mitochondrial lipid homeostasis

Phosphatidylcholine Affects Inner Membrane Protein Translocases of Mitochondria

Mitochondrial Membranes Restitution Proceeds via Vesicular Import from ER and Cytosol. Counterparts’ Resemblances and Variances in Mitochondria and Golgi Pathways

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