scholarly journals Organization of the Respiratory Supercomplexes in Cells with Defective Complex III: Structural Features and Metabolic Consequences

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 351
Author(s):  
Michela Rugolo ◽  
Claudia Zanna ◽  
Anna Maria Ghelli
Keyword(s):  
Atp Synthesis ◽  
Mitochondrial Respiratory Chain ◽  
Structural Features ◽  
Genetic Alterations ◽  
Complex Iii ◽  
Protonmotive Force ◽  
Metabolic Disturbances ◽  
Single Protein ◽  
Assembly Features ◽  
Supramolecular Aggregates

The mitochondrial respiratory chain encompasses four oligomeric enzymatic complexes (complex I, II, III and IV) which, together with the redox carrier ubiquinone and cytochrome c, catalyze electron transport coupled to proton extrusion from the inner membrane. The protonmotive force is utilized by complex V for ATP synthesis in the process of oxidative phosphorylation. Respiratory complexes are known to coexist in the membrane as single functional entities and as supramolecular aggregates or supercomplexes (SCs). Understanding the assembly features of SCs has relevant biomedical implications because defects in a single protein can derange the overall SC organization and compromise the energetic function, causing severe mitochondrial disorders. Here we describe in detail the main types of SCs, all characterized by the presence of complex III. We show that the genetic alterations that hinder the assembly of Complex III, not just the activity, cause a rearrangement of the architecture of the SC that can help to preserve a minimal energetic function. Finally, the major metabolic disturbances associated with severe SCs perturbation due to defective complex III are discussed along with interventions that may circumvent these deficiencies.

Structural and Spectroscopic Study of Langmuir-Schäfer Films of Bis Zn-Ethane-Bridged Porphyrins Dimer

2003 ◽  
Vol 771 ◽  
Author(s):  
G. Panzera ◽  
S. Conoci ◽  
S. Coffa ◽  
B. Pignataro ◽  
S. Sortino ◽  
...  
Keyword(s):  
Surface Pressure ◽  
Scanning Force Microscopy ◽  
Structural Features ◽  
Solid Surfaces ◽  
Condensed Phases ◽  
Brewster Angle Microscopy ◽  
Force Microscopy ◽  
Vis Spectroscopy ◽  
Scanning Force ◽  
Supramolecular Aggregates

AbstractThin films (1-24 layers) of bis-zinc ethane-bridged porphyrin dimer (1) have been transferred on solid surfaces, by the Langmuir- Schäfer (LS) horizontal method. The related surface pressurearea isotherm curve shows that in dependence of the film pressure different condensed phases may occur in the monolayer. The inspection of the monolayer by Brewster Angle Microscopy (BAM) reveals the presence of peculiar networks whose structural features seemingly change upon film compression. On the other hand, the Scanning Force Microscopy (SFM) analysis performed on LS films shows fractal networks constituted by nanoscopic supramolecular aggregates, whose shape and size depend again on the LS deposition surface pressure. Finally, also UV-vis spectroscopy measurements indicates that the absorption is almost linearly related to the film thickness that is directly connected to the surface pressure.

scholarly journals Specific requirements of nonbilayer phospholipids in mitochondrial respiratory chain function and formation

2016 ◽  
Vol 27 (14) ◽  
pp. 2161-2171 ◽  
Author(s):  
Charli D. Baker ◽  
Writoban Basu Ball ◽  
Erin N. Pryce ◽  
Vishal M. Gohil
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Membrane ◽  
Phospholipid Composition ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Specific Requirement ◽  
Transport Pathway ◽  
Contact Sites ◽  
Yeast Mutants ◽  
Mitochondrial Respiratory

Mitochondrial membrane phospholipid composition affects mitochondrial function by influencing the assembly of the mitochondrial respiratory chain (MRC) complexes into supercomplexes. For example, the loss of cardiolipin (CL), a signature non–bilayer-forming phospholipid of mitochondria, results in disruption of MRC supercomplexes. However, the functions of the most abundant mitochondrial phospholipids, bilayer-forming phosphatidylcholine (PC) and non–bilayer-forming phosphatidylethanolamine (PE), are not clearly defined. Using yeast mutants of PE and PC biosynthetic pathways, we show a specific requirement for mitochondrial PE in MRC complex III and IV activities but not for their formation, whereas loss of PC does not affect MRC function or formation. Unlike CL, mitochondrial PE or PC is not required for MRC supercomplex formation, emphasizing the specific requirement of CL in supercomplex assembly. Of interest, PE biosynthesized in the endoplasmic reticulum (ER) can functionally substitute for the lack of mitochondrial PE biosynthesis, suggesting the existence of PE transport pathway from ER to mitochondria. To understand the mechanism of PE transport, we disrupted ER–mitochondrial contact sites formed by the ERMES complex and found that, although not essential for PE transport, ERMES facilitates the efficient rescue of mitochondrial PE deficiency. Our work highlights specific roles of non–bilayer-forming phospholipids in MRC function and formation.

scholarly journals Assembly factors monitor sequential hemylation of cytochrome b to regulate mitochondrial translation

2014 ◽  
Vol 205 (4) ◽  
pp. 511-524 ◽  
Author(s):  
Markus Hildenbeutel ◽  
Eric L. Hegg ◽  
Katharina Stephan ◽  
Steffi Gruschke ◽  
Brigitte Meunier ◽  
...  
Keyword(s):  
Electron Transport ◽  
Cytochrome B ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Mitochondrial Translation ◽  
Respiratory Chain Complexes ◽  
Mitochondrial Inner Membrane ◽  
Sequence Of Events ◽  
Chain Complexes ◽  
Assembly Factors

Mitochondrial respiratory chain complexes convert chemical energy into a membrane potential by connecting electron transport with charge separation. Electron transport relies on redox cofactors that occupy strategic positions in the complexes. How these redox cofactors are assembled into the complexes is not known. Cytochrome b, a central catalytic subunit of complex III, contains two heme bs. Here, we unravel the sequence of events in the mitochondrial inner membrane by which cytochrome b is hemylated. Heme incorporation occurs in a strict sequential process that involves interactions of the newly synthesized cytochrome b with assembly factors and structural complex III subunits. These interactions are functionally connected to cofactor acquisition that triggers the progression of cytochrome b through successive assembly intermediates. Failure to hemylate cytochrome b sequesters the Cbp3–Cbp6 complex in early assembly intermediates, thereby causing a reduction in cytochrome b synthesis via a feedback loop that senses hemylation of cytochrome b.

Succinimidyl oleate, established inhibitor of CD36/FAT translocase inhibits complex III of mitochondrial respiratory chain

2010 ◽  
Vol 391 (3) ◽  
pp. 1348-1351 ◽  
Author(s):  
Zdeněk Drahota ◽  
Marek Vrbacký ◽  
Hana Nůsková ◽  
Ludmila Kazdová ◽  
Václav Zídek ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Mitochondrial Respiratory

Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A

Parasitology ◽  
2015 ◽  
Vol 142 (9) ◽  
pp. 1239-1248 ◽  
Author(s):  
LIANET MONZOTE ◽  
ALEXANDRA LACKOVA ◽  
KATRIN STANIEK ◽  
OSMANY CUESTA-RUBIO ◽  
LARS GILLE
Keyword(s):  
Mitochondrial Respiratory Chain ◽  
Peritoneal Macrophages ◽  
Complex Iii ◽  
Specific Inhibition ◽  
Mitochondrial Superoxide ◽  
Phloroglucinol Derivatives ◽  
Succinate:Ubiquinone Oxidoreductase ◽  
Species Specific ◽  
Mammalian Toxicity

SUMMARYNemorosone (Nem) and guttiferone A (GutA) are acyl phloroglucinol derivatives (APD) that are present in different natural products. For both compounds anti-cancer and anti-microbial properties have been reported. In particular, an anti-leishmanial activity of both compounds was demonstrated. The aim of this study was to explore the possible role of mitochondria in the anti-leishmanial activity of Nem and GutA in comparison with their action on mammalian mitochondria. Both APD inhibited the growth of promastigotes ofLeishmania tarentolae(LtP) with half maximal inhibitory concentration (IC50) values of 0·67 ± 0·17 and 6·2 ± 2·6μm; while IC50values for cytotoxicity against peritoneal macrophages from BALB/c mice were of 29·5 ± 3·7 and 9·2 ± 0·9μm, respectively. Nemorosone strongly inhibited LtP oxygen consumption, caused species-specific inhibition (P< 0·05) of succinate:ubiquinone oxidoreductase (complex II) from LtP-mitochondria and significantly increased (P< 0·05) the mitochondrial superoxide production. In contrast, GutA caused only a moderate reduction of respiration in LtP and triggered less superoxide radical production in LtP compared with Nem. In addition, GutA inhibited mitochondrial complex III in bovine heart submitochondrial particles, which is possibly involved in its mammalian toxicity. Both compounds demonstrated at low micromolar concentrations an effect on the mitochondrial membrane potential in LtP. The present study suggests that Nem caused its anti-leishmanial action due to specific inhibition of complexes II/III of mitochondrial respiratory chain ofLeishmaniaparasites that could be responsible for increased production of reactive oxygen species that triggers parasite death.

Complex III Mitochondrial Leukoencephalopathy Masquerading Acute Demyelinating Syndrome Due to a Novel Variant in CYC1

2021 ◽  
Author(s):  
Erfan Heidari ◽  
Maryam Rasoulinezhad ◽  
Neda Pak ◽  
Mahmoud Reza Ashrafi ◽  
Morteza Heidari ◽  
...  
Keyword(s):  
Vision Loss ◽  
Nuclear Dna ◽  
Missense Variant ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Clinical Spectrum ◽  
Neurological Deficits ◽  
Respiratory Chain Complexes ◽  
Mitochondrial Inner Membrane ◽  
Novel Variant

Abstract Background Complex III (CIII) is the third out of five mitochondrial respiratory chain complexes residing at the mitochondrial inner membrane. The assembly of 10 subunits encoded by nuclear DNA and one by mitochondrial DNA result in the functional CIII which transfers electrons from ubiquinol to cytochrome c. Deficiencies of CIII are among the least investigated mitochondrial disorders and thus clinical spectrum of patients with mutations in CIII is not well defined. Resultswe report on a 10-year-old girl born to consanguineous Iranian parents presenting with acute neurological deficits reminiscent of acquired demyelination, mainly acute bilateral vision loss, who was ultimately confirmed to have a novel homozygous missense variant, c.949C>T; p.(Arg317Trp) in complex III of the mitochondrial chain. Sanger sequencing confirmed the segregation of this variant with disease in the family. ConclusionWe present a patient with a mitochondrial leukoencephalopathy due to complex III deficiency that manifested with features suggestive of an acquired demyelinating syndrome. The effect of this variant on the protein structure was shown in-silico. Our findings, not only expand the clinical spectrum due to defects in CYC1 gene but also highlight that mitochondrial disease should be considered in children with acute CNS demyelination.

scholarly journals Novel Role of ATPase Subunit C Targeting Peptides Beyond Mitochondrial Protein Import

2010 ◽  
Vol 21 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Cristofol Vives-Bauza ◽  
Jordi Magrané ◽  
Antoni L. Andreu ◽  
Giovanni Manfredi
Keyword(s):  
Respiratory Chain ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Atp Synthesis ◽  
Mitochondrial Respiratory Chain ◽  
Genetic Redundancy ◽  
Mitochondrial Protein Import ◽  
Atpase Subunit ◽  
Subunit C ◽  
And Function

In mammals, subunit c of the F1F0-ATP synthase has three isoforms (P1, P2, and P3). These isoforms differ by their cleavable mitochondrial targeting peptides, whereas the mature peptides are identical. To investigate this apparent genetic redundancy, we knocked down each of the three subunit c isoform by RNA interference in HeLa cells. Silencing any of the subunit c isoforms individually resulted in an ATP synthesis defect, indicating that these isoforms are not functionally redundant. We found that subunit c knockdown impaired the structure and function of the mitochondrial respiratory chain. In particular, P2 silencing caused defective cytochrome oxidase assembly and function. Because the expression of exogenous P1 or P2 was able to rescue the respective silencing phenotypes, but the two isoforms were unable to cross-complement, we hypothesized that their functional specificity resided in their targeting peptides. In fact, the expression of P1 and P2 targeting peptides fused to GFP variants rescued the ATP synthesis and respiratory chain defects in the silenced cells. Our results demonstrate that the subunit c isoforms are nonredundant, because they differ functionally by their targeting peptides, which, in addition to mediating mitochondrial protein import, play a yet undiscovered role in respiratory chain maintenance.

scholarly journals Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I)

2018 ◽  
Vol 399 (11) ◽  
pp. 1249-1264 ◽  
Author(s):  
Tomoko Ohnishi ◽  
S. Tsuyoshi Ohnishi ◽  
John C. Salerno
Keyword(s):  
Electron Transfer ◽  
Respiratory Chain ◽  
Complex I ◽  
Proton Translocation ◽  
Atp Synthesis ◽  
Mitochondrial Respiratory Chain ◽  
Proton Pumping ◽  
Entry Site ◽  
Quinone Oxidoreductase ◽  
Terminal Electron Acceptor

AbstractNADH-quinone oxidoreductase (complex I) is the largest and most complicated enzyme complex of the mitochondrial respiratory chain. It is the entry site into the respiratory chain for most of the reducing equivalents generated during metabolism, coupling electron transfer from NADH to quinone to proton translocation, which in turn drives ATP synthesis. Dysfunction of complex I is associated with neurodegenerative diseases such as Parkinson’s and Alzheimer’s, and it is proposed to be involved in aging. Complex I has one non-covalently bound FMN, eight to 10 iron-sulfur clusters, and protein-associated quinone molecules as electron transport components. Electron paramagnetic resonance (EPR) has previously been the most informative technique, especially in membranein situanalysis. The structure of complex 1 has now been resolved from a number of species, but the mechanisms by which electron transfer is coupled to transmembrane proton pumping remains unresolved. Ubiquinone-10, the terminal electron acceptor of complex I, is detectable by EPR in its one electron reduced, semiquinone (SQ) state. In the aerobic steady state of respiration the semi-ubiquinone anion has been observed and studied in detail. Two distinct protein-associated fast and slow relaxing, SQ signals have been resolved which were designated SQNfand SQNs. This review covers a five decade personal journey through the field leading to a focus on the unresolved questions of the role of the SQ radicals and their possible part in proton pumping.

The molecular machinery of Keilin's respiratory chain

2003 ◽  
Vol 31 (6) ◽  
pp. 1095-1105 ◽  
Author(s):  
P.R. Rich
Keyword(s):  
Respiratory Chain ◽  
Atp Synthesis ◽  
Mitochondrial Respiratory Chain ◽  
New Era ◽  
Current State ◽  
Molecular Machinery ◽  
Tremendous Amount ◽  
Health And Disease ◽  
Level I ◽  
Prosthetic Groups

Keilin's classic paper of 1925 [Keilin (1925) Proc. R. Soc. London Ser. B 100, 129–151], achieved with simple, but elegant, techniques, describes the cytochrome components of the respiratory chain and their roles in intracellular respiration and oxygen consumption. Since that time, a tremendous amount of work has clarified the intricate details of the prosthetic groups, cofactors and proteins that comprise the respiratory chain and associated machinery for ATP synthesis. The work has culminated in advanced crystallographic and spectroscopic methods that provide structural and mechanistic details of this mitochondrial molecular machinery, in many instances to atomic level. I review here the current state of understanding of the mitochondrial respiratory chain in terms of structures and dynamics of the component proteins and their roles in the biological electron and proton transfer processes that result in ATP synthesis. These advances, together with emerging evidence of further diverse roles of mitochondria in health and disease, have prompted a new era of interest in mitochondrial function.

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