scholarly journals Selective and Reversible Disruption of Mitochondrial Inner Membrane Protein Complexes by Lipophilic Cations

2021 ◽  
Author(s):  
Anezka Kafkova ◽  
Lisa Tilokani ◽  
Filip Trčka ◽  
Veronika Šrámková ◽  
Marie Vancová ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Respiratory Chain ◽  
Mitochondrial Membrane ◽  
Mitochondrial Morphology ◽  
Respiratory Chain Complexes ◽  
Inner Membrane ◽  
Protein Levels ◽  
Mitochondrial Inner Membrane ◽  
Chain Complexes ◽  
The Impact

ABSTRACTMitochondria represent an attractive drug target in the treatment of many diseases. One of the most commonly used approaches to deliver therapeutics specifically into mitochondria is their conjugation to the triphenylphosphonium (TPP) moiety. While the TPP molecule is often regarded as biologically inert, there is evidence that the moiety itself has a significant impact on the activity of mitochondrial respiratory chain complexes.We studied the impact of a subchronic exposure of C2C12 mouse myoblasts to a set of TPP derivatives. Our results show that the alkyl-TPP cause dose- and hydrophobicity-dependent alterations of mitochondrial morphology and a selective decrease in the amounts of mitochondrial inner membrane (but not outer membrane) proteins including structural subunits of the respiratory chain complexes (such as MT-CO1 of complex IV or NDUFB8 of complex I), as well as components of the mitochondrial calcium uniporter complex (MCUC). The treatment with alkyl-TPP additionally resulted in OPA1-cleavage. Both the structural and functional effects of alkyl-TPP were found to be reversible. A similar effect was observed with the mitochondria-targeted antioxidant MitoQ. We further show that this effect on protein levels cannot be explained solely by a decrease in mitochondrial membrane potential.We conclude that TPP derivatives negatively affect mitochondrial structure and function at least in part through their effect on selective mitochondrial membrane protein levels via a reversible controlled process.

scholarly journals Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

2005 ◽  
Vol 16 (11) ◽  
pp. 5202-5214 ◽  
Author(s):  
Katrin Brandner ◽  
David U. Mick ◽  
Ann E. Frazier ◽  
Rebecca D. Taylor ◽  
Chris Meisinger ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Respiratory Chain ◽  
Mitochondrial Membrane ◽  
Barth Syndrome ◽  
Outer Mitochondrial Membrane ◽  
Respiratory Chain Complexes ◽  
Complex Iv ◽  
Inner Membrane ◽  
Chain Complexes ◽  
Mitochondrial Membrane Protein

The Saccharomyces cerevisiae Taz1 protein is the orthologue of human Tafazzin, a protein that when inactive causes Barth Syndrome (BTHS), a severe inherited X-linked disease. Taz1 is a mitochondrial acyltransferase involved in the remodeling of cardiolipin. We show that Taz1 is an outer mitochondrial membrane protein exposed to the intermembrane space (IMS). Transport of Taz1 into mitochondria depends on the receptor Tom5 of the translocase of the outer membrane (TOM complex) and the small Tim proteins of the IMS, but is independent of the sorting and assembly complex (SAM). TAZ1 deletion in yeast leads to growth defects on nonfermentable carbon sources, indicative of a defect in respiration. Because cardiolipin has been proposed to stabilize supercomplexes of the respiratory chain complexes III and IV, we assess supercomplexes in taz1Δ mitochondria and show that these are destabilized in taz1Δ mitochondria. This leads to a selective release of a complex IV monomer from the III2IV2 supercomplex. In addition, assembly analyses of newly imported subunits into complex IV show that incorporation of the complex IV monomer into supercomplexes is affected in taz1Δ mitochondria. We conclude that inactivation of Taz1 affects both assembly and stability of respiratory chain complexes in the inner membrane of mitochondria.

scholarly journals YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation

2012 ◽  
Vol 23 (6) ◽  
pp. 1010-1023 ◽  
Author(s):  
Lukas Stiburek ◽  
Jana Cesnekova ◽  
Olga Kostkova ◽  
Daniela Fornuskova ◽  
Kamila Vinsova ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Membrane Protein ◽  
Respiratory Chain ◽  
Integral Membrane Protein ◽  
Intermembrane Space ◽  
Wild Type ◽  
Inner Membrane ◽  
Mitochondrial Inner Membrane ◽  
Human Orthologue ◽  
Excessive Accumulation

Mitochondrial ATPases associated with diverse cellular activities (AAA) proteases are involved in the quality control and processing of inner-membrane proteins. Here we investigate the cellular activities of YME1L, the human orthologue of the Yme1 subunit of the yeast i‑AAA complex, using stable short hairpin RNA knockdown and expression experiments. Human YME1L is shown to be an integral membrane protein that exposes its carboxy-terminus to the intermembrane space and exists in several complexes of 600–1100 kDa. The stable knockdown of YME1L in human embryonic kidney 293 cells led to impaired cell proliferation and apoptotic resistance, altered cristae morphology, diminished rotenone-sensitive respiration, and increased susceptibility to mitochondrial membrane protein carbonylation. Depletion of YME1L led to excessive accumulation of nonassembled respiratory chain subunits (Ndufb6, ND1, and Cox4) in the inner membrane. This was due to a lack of YME1L proteolytic activity, since the excessive accumulation of subunits was reversed by overexpression of wild-type YME1L but not a proteolytically inactive YME1L variant. Similarly, the expression of wild-type YME1L restored the lamellar cristae morphology of YME1L-deficient mitochondria. Our results demonstrate the importance of mitochondrial inner-membrane proteostasis to both mitochondrial and cellular function and integrity and reveal a novel role for YME1L in the proteolytic regulation of respiratory chain biogenesis.

scholarly journals Mitochondrial Membrane Dynamics—Functional Positioning of OPA1

Antioxidants ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 186 ◽  
Author(s):  
Hakjoo Lee ◽  
Yisang Yoon
Keyword(s):  
Mitochondrial Membrane ◽  
Proteolytic Cleavage ◽  
Membrane Dynamics ◽  
Mitochondrial Morphology ◽  
Inner Membrane ◽  
Mitochondrial Inner Membrane ◽  
Functional Differences ◽  
New Information ◽  
New Development

The maintenance of mitochondrial energetics requires the proper regulation of mitochondrial morphology, and vice versa. Mitochondrial dynamins control mitochondrial morphology by mediating fission and fusion. One of them, optic atrophy 1 (OPA1), is the mitochondrial inner membrane remodeling protein. OPA1 has a dual role in maintaining mitochondrial morphology and energetics through mediating inner membrane fusion and maintaining the cristae structure. OPA1 is expressed in multiple variant forms through alternative splicing and post-translational proteolytic cleavage, but the functional differences between these variants have not been completely understood. Recent studies generated new information regarding the role of OPA1 cleavage. In this review, we will first provide a brief overview of mitochondrial membrane dynamics by describing fission and fusion that are mediated by mitochondrial dynamins. The second part describes OPA1-mediated fusion and energetic maintenance, the role of OPA1 cleavage, and a new development in OPA1 function, in which we will provide new insight for what OPA1 does and what proteolytic cleavage of OPA1 is for.

scholarly journals Ribosome-binding Proteins Mdm38 and Mba1 Display Overlapping Functions for Regulation of Mitochondrial Translation

2010 ◽  
Vol 21 (12) ◽  
pp. 1937-1944 ◽  
Author(s):  
Heike Bauerschmitt ◽  
David U. Mick ◽  
Markus Deckers ◽  
Christine Vollmer ◽  
Soledad Funes ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Respiratory Chain ◽  
Membrane Insertion ◽  
Mitochondrial Translation ◽  
Respiratory Chain Complexes ◽  
Ribosome Binding ◽  
Chain Complexes ◽  
Inner Membrane Protein ◽  
Simultaneous Loss ◽  
Regulatory Functions

Biogenesis of respiratory chain complexes depends on the expression of mitochondrial-encoded subunits. Their synthesis occurs on membrane-associated ribosomes and is probably coupled to their membrane insertion. Defects in expression of mitochondrial translation products are among the major causes of mitochondrial disorders. Mdm38 is related to Letm1, a protein affected in Wolf-Hirschhorn syndrome patients. Like Mba1 and Oxa1, Mdm38 is an inner membrane protein that interacts with ribosomes and is involved in respiratory chain biogenesis. We find that simultaneous loss of Mba1 and Mdm38 causes severe synthetic defects in the biogenesis of cytochrome reductase and cytochrome oxidase. These defects are not due to a compromised membrane binding of ribosomes but the consequence of a mis-regulation in the synthesis of Cox1 and cytochrome b. Cox1 expression is restored by replacing Cox1-specific regulatory regions in the mRNA. We conclude, that Mdm38 and Mba1 exhibit overlapping regulatory functions in translation of selected mitochondrial mRNAs.

scholarly journals IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 158
Author(s):  
Susana Cardoso ◽  
Icíar López ◽  
Sergio Piñeiro-Hermida ◽  
José Pichel ◽  
Paula Moreira
Keyword(s):  
Signaling Pathways ◽  
Mitochondrial Dynamics ◽  
Redox Homeostasis ◽  
Mitochondrial Respiratory Chain ◽  
Related Factor ◽  
Respiratory Chain Complexes ◽  
Protein Levels ◽  
Chain Complexes ◽  
The Impact ◽  
The Brain

Insulin-like growth factor 1 receptor (IGF1R)-mediated signaling pathways modulate important neurophysiological aspects in the central nervous system, including neurogenesis, synaptic plasticity and complex cognitive functions. In the present study, we intended to characterize the impact of IGF1R deficiency in the brain, focusing on PI3K/Akt and MAPK/ERK1/2 signaling pathways and mitochondria-related parameters. For this purpose, we used 13-week-old UBC-CreERT2; Igf1rfl/fl male mice in which Igf1r was conditionally deleted. IGF1R deficiency caused a decrease in brain weight as well as the activation of the IR/PI3K/Akt and inhibition of the MAPK/ERK1/2/CREB signaling pathways. Despite no alterations in the activity of caspases 3 and 9, a significant alteration in phosphorylated GSK3β and an increase in phosphorylated Tau protein levels were observed. In addition, significant disturbances in mitochondrial dynamics and content and altered activity of the mitochondrial respiratory chain complexes were noticed. An increase in oxidative stress, characterized by decreased nuclear factor E2-related factor 2 (NRF2) protein levels and aconitase activity and increased H2O2 levels were also found in the brain of IGF1R-deficient mice. Overall, our observations confirm the complexity of IGF1R in mediating brain signaling responses and suggest that its deficiency negatively impacts brain cells homeostasis and survival by affecting mitochondria and redox homeostasis.

scholarly journals Mitochondrial DNA Depletion and Respiratory Chain Activity in Primary Human Subcutaneous Adipocytes Treated with Nucleoside Analogue Reverse Transcriptase Inhibitors

2009 ◽  
Vol 54 (1) ◽  
pp. 280-287 ◽  
Author(s):  
Metodi V. Stankov ◽  
Thomas Lücke ◽  
Anibh M. Das ◽  
Reinhold E. Schmidt ◽  
Georg M. N. Behrens
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Respiratory Chain ◽  
Mitochondrial Membrane ◽  
Reverse Transcriptase Inhibitors ◽  
Respiratory Chain Complexes ◽  
Mitochondrial Mass ◽  
Mtdna Depletion ◽  
Chain Complexes ◽  
Respiratory Chain Activity

ABSTRACT Mitochondrial dysfunction as a consequence of mitochondrial DNA (mtDNA) depletion due to therapy with nucleoside analogue reverse transcriptase inhibitors (NRTI) has been proposed as a pathogenic mechanism leading to lipoatrophy in HIV-infected patients. The aim of our study was to investigate the impact of NRTI treatment on mtDNA abundance and the activities of respiratory chain complexes in primary human subcutaneous preadipocytes (phsPA). We studied adipocyte phenotypes, viability, and differentiation (CCAAT/enhancer-binding protein α [C/EBPα] and peroxisome proliferator-activated receptor γ [PPARγ] expression) and adiponectin production, mtDNA content, mitochondrial membrane potential, mitochondrial mass, and respiratory chain enzyme and citrate synthase activities in both proliferating and differentiating phsPA. Cells were exposed to zidovudine (6 μM), stavudine (d4T; 3 μM), and zalcitabine (ddC; 0.1 μM) for 8 weeks. NRTI-induced mtDNA depletion occurred in proliferating and differentiating phsPA after exposure to therapeutic drug concentrations of d4T and ddC. At these concentrations, ddC and d4T led to an almost 50% decrease in the number of mtDNA copies per cell without major impact on adipocyte differentiation. Despite mtDNA depletion by NRTI, the activities of the respiratory chain complexes, the mitochondrial membrane potential, and the mitochondrial mass were found to be unaffected. Severe NRTI-mediated mtDNA depletion in phsPA is not inevitably associated with impaired respiratory chain activity or altered mitochondrial membrane potential.

scholarly journals Roles of Oxa1-related inner-membrane translocases in assembly of respiratory chain complexes

2009 ◽  
Vol 1793 (1) ◽  
pp. 60-70 ◽  
Author(s):  
Nathalie Bonnefoy ◽  
Heather L. Fiumera ◽  
Geneviève Dujardin ◽  
Thomas D. Fox
Keyword(s):  
Respiratory Chain ◽  
Respiratory Chain Complexes ◽  
Inner Membrane ◽  
Chain Complexes

scholarly journals The novel conserved mitochondrial inner-membrane protein MTGM regulates mitochondrial morphology and cell proliferation

2009 ◽  
Vol 122 (13) ◽  
pp. 2252-2262 ◽  
Author(s):  
J. Zhao ◽  
T. Liu ◽  
S.-B. Jin ◽  
N. Tomilin ◽  
J. Castro ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Membrane Protein ◽  
Mitochondrial Morphology ◽  
The Novel ◽  
Inner Membrane ◽  
Mitochondrial Inner Membrane ◽  
Inner Membrane Protein

Age-related changes in the activities of respiratory chain complexes and mitochondrial morphology in Drosophila

Mitochondrion ◽  
2012 ◽  
Vol 12 (2) ◽  
pp. 345-351 ◽  
Author(s):  
Yukiko Oda ◽  
Ryoko Yui ◽  
Kimitoshi Sakamoto ◽  
Kiyoshi Kita ◽  
Etsuko T. Matsuura
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Morphology ◽  
Respiratory Chain Complexes ◽  
Age Related ◽  
Chain Complexes ◽  
Age Related Changes
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