scholarly journals The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I

2022 ◽  
Vol 8 ◽  
Author(s):  
Abhilash Padavannil ◽  
Maria G. Ayala-Hernandez ◽  
Eimy A. Castellanos-Silva ◽  
James A. Letts
Keyword(s):  
Clinical Studies ◽  
Complex I ◽  
Protein Production ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Inner Mitochondrial Membrane ◽  
Complete Understanding ◽  
Transport Chain ◽  
Accessory Subunits ◽  
Respiratory Complex I ◽  
And Function

Complex I (CI) is the largest protein complex in the mitochondrial oxidative phosphorylation electron transport chain of the inner mitochondrial membrane and plays a key role in the transport of electrons from reduced substrates to molecular oxygen. CI is composed of 14 core subunits that are conserved across species and an increasing number of accessory subunits from bacteria to mammals. The fact that adding accessory subunits incurs costs of protein production and import suggests that these subunits play important physiological roles. Accordingly, knockout studies have demonstrated that accessory subunits are essential for CI assembly and function. Furthermore, clinical studies have shown that amino acid substitutions in accessory subunits lead to several debilitating and fatal CI deficiencies. Nevertheless, the specific roles of CI’s accessory subunits have remained mysterious. In this review, we explore the possible roles of each of mammalian CI’s 31 accessory subunits by integrating recent high-resolution CI structures with knockout, assembly, and clinical studies. Thus, we develop a framework of experimentally testable hypotheses for the function of the accessory subunits. We believe that this framework will provide inroads towards the complete understanding of mitochondrial CI physiology and help to develop strategies for the treatment of CI deficiencies.

scholarly journals High-resolution cryo-EM structures of respiratory complex I: Mechanism, assembly, and disease

2019 ◽  
Vol 5 (12) ◽  
pp. eaax9484 ◽  
Author(s):  
Kristian Parey ◽  
Outi Haapanen ◽  
Vivek Sharma ◽  
Harald Köfeler ◽  
Thomas Züllig ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Membrane ◽  
Electrochemical Gradient ◽  
Inner Mitochondrial Membrane ◽  
Respiratory Complex ◽  
Access Path ◽  
Respiratory Complex I ◽  
Assembly Intermediate ◽  
The One ◽  
Complex I Assembly

Respiratory complex I is a redox-driven proton pump, accounting for a large part of the electrochemical gradient that powers mitochondrial adenosine triphosphate synthesis. Complex I dysfunction is associated with severe human diseases. Assembly of the one-megadalton complex I in the inner mitochondrial membrane requires assembly factors and chaperones. We have determined the structure of complex I from the aerobic yeast Yarrowia lipolytica by electron cryo-microscopy at 3.2-Å resolution. A ubiquinone molecule was identified in the access path to the active site. The electron cryo-microscopy structure indicated an unusual lipid-protein arrangement at the junction of membrane and matrix arms that was confirmed by molecular simulations. The structure of a complex I mutant and an assembly intermediate provide detailed molecular insights into the cause of a hereditary complex I–linked disease and complex I assembly in the inner mitochondrial membrane.

scholarly journals Oxidation and reduction of pyridine nucleotides in alamethicin-permeabilized plant mitochondria

2004 ◽  
Vol 380 (1) ◽  
pp. 193-202 ◽  
Author(s):  
Fredrik I. JOHANSSON ◽  
Agnieszka M. MICHALECKA ◽  
Ian M. MØLLER ◽  
Allan G. RASMUSSON
Keyword(s):  
Electron Transport ◽  
Complex I ◽  
Electron Transport Chain ◽  
Nadh Dehydrogenase ◽  
Plant Mitochondria ◽  
Inner Mitochondrial Membrane ◽  
Intact Cells ◽  
Transport Chain ◽  
Invasive Method

The inner mitochondrial membrane is selectively permeable, which limits the transport of solutes and metabolites across the membrane. This constitutes a problem when intramitochondrial enzymes are studied. The channel-forming antibiotic AlaM (alamethicin) was used as a potentially less invasive method to permeabilize mitochondria and study the highly branched electron-transport chain in potato tuber (Solanum tuberosum) and pea leaf (Pisum sativum) mitochondria. We show that AlaM permeabilized the inner membrane of plant mitochondria to NAD(P)H, allowing the quantification of internal NAD(P)H dehydrogenases as well as matrix enzymes in situ. AlaM was found to inhibit the electron-transport chain at the external Ca2+-dependent rotenone-insensitive NADH dehydrogenase and around complexes III and IV. Nevertheless, under optimal conditions, especially complex I-mediated NADH oxidation in AlaM-treated mitochondria was much higher than what has been previously measured by other techniques. Our results also show a difference in substrate specificities for complex I in mitochondria as compared with inside-out submitochondrial particles. AlaM facilitated the passage of cofactors to and from the mitochondrial matrix and allowed the determination of NAD+ requirements of malate oxidation in situ. In summary, we conclude that AlaM provides the best method for quantifying NADH dehydrogenase activities and that AlaM will prove to be an important method to study enzymes under conditions that resemble their native environment not only in plant mitochondria but also in other membrane-enclosed compartments, such as intact cells, chloroplasts and peroxisomes.

A single external enzyme confers alternative NADH:ubiquinone oxidoreductase activity in Yarrowia lipolytica

1999 ◽  
Vol 112 (14) ◽  
pp. 2347-2354 ◽  
Author(s):  
S.J. Kerscher ◽  
J.G. Okun ◽  
U. Brandt
Keyword(s):  
Yarrowia Lipolytica ◽  
Complex I ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Inner Mitochondrial Membrane ◽  
Gene Encoding ◽  
Oxidoreductase Activity ◽  
Mitochondrial Inner Membrane ◽  
Energy Conserving ◽  
And Function ◽  
Complex I Activity

NADH:ubiquinone oxidoreductases catalyse the first step within the diverse pathways of mitochondrial NADH oxidation. In addition to the energy-conserving form commonly called complex I, fungi and plants contain much simpler alternative NADH:ubiquinone oxido-reductases that catalyze the same reaction but do not translocate protons across the inner mitochondrial membrane. Little is known about the distribution and function of these enzymes. We have identified YLNDH2 as the only gene encoding an alternative NADH:ubiquinone oxidoreductase (NDH2) in the obligate aerobic yeast Yarrowia lipolytica. Cells carrying a deletion of YLNDH2 were fully viable; full inhibition by piericidin A indicated that complex I activity was the sole NADH:ubiquinone oxidoreductase activity left in the deletion strains. Studies with intact mitochondria revealed that NDH2 in Y. lipolytica is oriented towards the external face of the mitochondrial inner membrane. This is in contrast to the situation seen in Saccharomyces cerevisiae, Neurospora crassa and in green plants, where internal alternative NADH:ubiquinone oxidoreductases have been reported. Phylogenetic analysis of known NADH:ubiquinone oxidoreductases suggests that during evolution conversion of an ancestral external alternative NADH:ubiquinone oxidoreductase to an internal enzyme may have paved the way for the loss of complex I in fermenting yeasts like S. cerevisiae.

scholarly journals Accessory Subunits of the Matrix Arm of Mitochondrial Complex I with a Focus on Subunit NDUFS4 and Its Role in Complex I Function and Assembly

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 455
Author(s):  
Flora Kahlhöfer ◽  
Max Gansen ◽  
Volker Zickermann
Keyword(s):  
Complex I ◽  
Hot Spot ◽  
Proton Translocation ◽  
Chain Complex ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Inner Mitochondrial Membrane ◽  
Accessory Subunits ◽  
The Matrix ◽  
Assembly Factor ◽  
Accessory Subunit

NADH:ubiquinone-oxidoreductase (complex I) is the largest membrane protein complex of the respiratory chain. Complex I couples electron transfer to vectorial proton translocation across the inner mitochondrial membrane. The L shaped structure of complex I is divided into a membrane arm and a matrix arm. Fourteen central subunits are conserved throughout species, while some 30 accessory subunits are typically found in eukaryotes. Complex I dysfunction is associated with mutations in the nuclear and mitochondrial genome, resulting in a broad spectrum of neuromuscular and neurodegenerative diseases. Accessory subunit NDUFS4 in the matrix arm is a hot spot for mutations causing Leigh or Leigh-like syndrome. In this review, we focus on accessory subunits of the matrix arm and discuss recent reports on the function of accessory subunit NDUFS4 and its interplay with NDUFS6, NDUFA12, and assembly factor NDUFAF2 in complex I assembly.

scholarly journals The principal mitochondrial K+ uniport is associated with respiratory complex I

2022 ◽  
Author(s):  
Michael Zemel ◽  
Alessia Angelin ◽  
Prasanth Potluri ◽  
Douglas Wallace ◽  
Francesca Fieni
Keyword(s):  
Complex I ◽  
Adenosine Diphosphate ◽  
Proton Motive Force ◽  
Motive Force ◽  
Atp Production ◽  
Respiratory Complex ◽  
Diffusion Systems ◽  
Transport Chain ◽  
Respiratory Complex I ◽  
Vectorial Metabolism

Mitochondria generate ATP via coupling the negative electrochemical potential (proton motive force, Capital Greek (Deltap), consisting of a proton gradient (Capital Greek DeltapH+) and a membrane potential (Capital Greek Psim) across the respiratory chain, to phosphorylation of adenosine diphosphate nucleotide. In turn, DeltapH+ and Capital Greek Psim, are tightly balanced by the modulation of ionic uniporters and exchange-diffusion systems which preserve integrity of mitochondrial membranes and regulate ATP production. Here, we provide direct electrophysiological, pharmacological and genetic evidence that the main mitochondrial electrophoretic pathway for monovalent cations is associated with respiratory complex I, contrary to the long-held dogma that only H+ gradients are built across proteins of the mammalian electron transport chain. Here we propose a theoretical framework to describe how monovalent metal cations contribute to the buildup of H+ gradients and the proton motive force, extending the classical Mitchellian view on chemiosmosis and vectorial metabolism. Keywords: mitochondrial electrogenic transport, chemiosmotic theory, vectorial metabolism, whole-mitochondria electrophysiology.

scholarly journals Atomic structure of a mitochondrial complex I intermediate from vascular plants

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Maria Maldonado ◽  
Abhilash Padavannil ◽  
Long Zhou ◽  
Fei Guo ◽  
James A Letts
Keyword(s):  
Complex I ◽  
Vascular Plants ◽  
Protein Complexes ◽  
Structural Studies ◽  
Mitochondrial Complex ◽  
Transport Chain ◽  
Accessory Subunits ◽  
Membrane Protein Complexes ◽  
Assembly Intermediate ◽  
Membrane Anchoring

Respiration, an essential metabolic process, provides cells with chemical energy. In eukaryotes, respiration occurs via the mitochondrial electron transport chain (mETC) composed of several large membrane-protein complexes. Complex I (CI) is the main entry point for electrons into the mETC. For plants, limited availability of mitochondrial material has curbed detailed biochemical and structural studies of their mETC. Here, we present the cryoEM structure of the known CI assembly intermediate CI* from Vigna radiata at 3.9 Å resolution. CI* contains CI’s NADH-binding and CoQ-binding modules, the proximal-pumping module and the plant-specific γ-carbonic-anhydrase domain (γCA). Our structure reveals significant differences in core and accessory subunits of the plant complex compared to yeast, mammals and bacteria, as well as the details of the γCA domain subunit composition and membrane anchoring. The structure sheds light on differences in CI assembly across lineages and suggests potential physiological roles for CI* beyond assembly.

scholarly journals Accessory subunits are integral for assembly and function of human mitochondrial complex I

Nature ◽  
2016 ◽  
Vol 538 (7623) ◽  
pp. 123-126 ◽  
Author(s):  
David A. Stroud ◽  
Elliot E. Surgenor ◽  
Luke E. Formosa ◽  
Boris Reljic ◽  
Ann E. Frazier ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Accessory Subunits ◽  
And Function
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