scholarly journals TIMMDC1/C3orf1 Functions as a Membrane-Embedded Mitochondrial Complex I Assembly Factor through Association with the MCIA Complex

2013 ◽  
Vol 34 (5) ◽  
pp. 847-861 ◽  
Author(s):  
Virginia Guarani ◽  
Joao Paulo ◽  
Bo Zhai ◽  
Edward L. Huttlin ◽  
Steven P. Gygi ◽  
...  
Keyword(s):  
Complex I ◽  
Cellular Respiration ◽  
Inner Membrane ◽  
Atp Production ◽  
Mitochondrial Inner Membrane ◽  
Transport Chain ◽  
Assembly Factors ◽  
Assembly Factor ◽  
Interaction Proteomics ◽  
Complex I Assembly

Complex I (CI) of the electron transport chain, a large membrane-embedded NADH dehydrogenase, couples electron transfer to the release of protons into the mitochondrial inner membrane space to promote ATP production through ATP synthase. In addition to being a central conduit for ATP production, CI activity has been linked to neurodegenerative disorders, including Parkinson's disease. CI is built in a stepwise fashion through the actions of several assembly factors. We employed interaction proteomics to interrogate the molecular associations of 15 core subunits and assembly factors previously linked to human CI deficiency, resulting in a network of 101 proteins and 335 interactions (edges). TIMMDC1, a predicted 4-pass membrane protein, reciprocally associated with multiple members of the MCIA CI assembly factor complex and core CI subunits and was localized in the mitochondrial inner membrane, and its depletion resulted in reduced CI activity and cellular respiration. Quantitative proteomics demonstrated a role for TIMMDC1 in assembly of membrane-embedded and soluble arms of the complex. This study defines a new membrane-embedded CI assembly factor and provides a resource for further analysis of CI biology.

External alternative NADH:ubiquinone oxidoreductase redirected to the internal face of the mitochondrial inner membrane rescues complex I deficiency in Yarrowia lipolytica

2001 ◽  
Vol 114 (21) ◽  
pp. 3915-3921 ◽  
Author(s):  
Stefan J. Kerscher ◽  
Andrea Eschemann ◽  
Pamela M. Okun ◽  
Ulrich Brandt
Keyword(s):  
Yarrowia Lipolytica ◽  
Complex I ◽  
Functional Expression ◽  
Proton Pumping ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Inner Membrane ◽  
Mitochondrial Inner Membrane ◽  
The Matrix ◽  
Cytosolic Side ◽  
Respiratory Membrane

Alternative NADH:ubiquinone oxidoreductases are single subunit enzymes capable of transferring electrons from NADH to ubiquinone without contributing to the proton gradient across the respiratory membrane. The obligately aerobic yeast Yarrowia lipolytica has only one such enzyme, encoded by the NDH2 gene and located on the external face of the mitochondrial inner membrane. In sharp contrast to ndh2 deletions, deficiencies in nuclear genes for central subunits of proton pumping NADH:ubiquinone oxidoreductases (complex I) are lethal. We have redirected NDH2 to the internal face of the mitochondrial inner membrane by N-terminally attaching the mitochondrial targeting sequence of NUAM, the largest subunit of complex I. Lethality of complex I mutations was rescued by the internal, but not the external version of alternative NADH:ubiquinone oxidoreductase. Internal NDH2 also permitted growth in the presence of complex I inhibitors such as 2-decyl-4-quinazolinyl amine (DQA). Functional expression of NDH2 on both sides of the mitochondrial inner membrane indicates that alternative NADH:ubiquinone oxidoreductase requires no additional components for catalytic activity. Our findings also demonstrate that shuttle mechanisms for the transfer of redox equivalents from the matrix to the cytosolic side of the mitochondrial inner membrane are insufficient in Y. lipolytica.

scholarly journals Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency

2016 ◽  
Vol 99 (1) ◽  
pp. 208-216 ◽  
Author(s):  
Laura Sánchez-Caballero ◽  
Benedetta Ruzzenente ◽  
Lucas Bianchi ◽  
Zahra Assouline ◽  
Giulia Barcia ◽  
...  
Keyword(s):  
Muscle Weakness ◽  
Complex I ◽  
Complex I Deficiency ◽  
Assembly Factor ◽  
Complex I Assembly

scholarly journals C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved inbc1Complex Assembly and Supercomplex Stabilization

2015 ◽  
Vol 35 (7) ◽  
pp. 1139-1156 ◽  
Author(s):  
Marjorie Desmurs ◽  
Michelangelo Foti ◽  
Etienne Raemy ◽  
Frédéric Maxime Vaz ◽  
Jean-Claude Martinou ◽  
...  
Keyword(s):  
Intermembrane Space ◽  
Core Complex ◽  
Mitochondrial Inner Membrane ◽  
Transport Chain ◽  
Mammalian Mitochondria ◽  
Assembly Factor ◽  
Subsequent Elimination ◽  
Inner Membrane Protein ◽  
Selection Of ◽  
Higher Sensitivity

Mammalian mitochondria may contain up to 1,500 different proteins, and many of them have neither been confidently identified nor characterized. In this study, we demonstrated that C11orf83, which was lacking experimental characterization, is a mitochondrial inner membrane protein facing the intermembrane space. This protein is specifically associated with thebc1complex of the electron transport chain and involved in the early stages of its assembly by stabilizing thebc1core complex. C11orf83 displays some overlapping functions with Cbp4p, a yeastbc1complex assembly factor. Therefore, we suggest that C11orf83, now called UQCC3, is the functional human equivalent of Cbp4p. In addition, C11orf83 depletion in HeLa cells caused abnormal crista morphology, higher sensitivity to apoptosis, a decreased ATP level due to impaired respiration and subtle, but significant, changes in cardiolipin composition. We showed that C11orf83 binds to cardiolipin by its α-helices 2 and 3 and is involved in the stabilization ofbc1complex-containing supercomplexes, especially the III2/IV supercomplex. We also demonstrated that the OMA1 metalloprotease cleaves C11orf83 in response to mitochondrial depolarization, suggesting a role in the selection of cells with damaged mitochondria for their subsequent elimination by apoptosis, as previously described for OPA1.

Identification and functional analysis of mitochondrial complex I assembly factor homologues in C. elegans

Mitochondrion ◽  
2012 ◽  
Vol 12 (3) ◽  
pp. 399-405 ◽  
Author(s):  
Daniela van den Ecker ◽  
Mariël A. van den Brand ◽  
Gerke Ariaans ◽  
Michael Hoffmann ◽  
Olaf Bossinger ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Complex I ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
C Elegans ◽  
Assembly Factor ◽  
Complex I Assembly

Mutations in mitochondrial complex I assembly factor NDUFAF3 cause Leigh syndrome

2017 ◽  
Vol 120 (3) ◽  
pp. 243-246 ◽  
Author(s):  
Fabian Baertling ◽  
Laura Sánchez-Caballero ◽  
Sharita Timal ◽  
Mariël AM van den Brand ◽  
Lock Hock Ngu ◽  
...  
Keyword(s):  
Complex I ◽  
Leigh Syndrome ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Assembly Factor ◽  
Complex I Assembly

scholarly journals Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded subunits and interaction with prohibitin

2004 ◽  
Vol 383 (3) ◽  
pp. 491-499 ◽  
Author(s):  
Ingrid BOURGES ◽  
Claire RAMUS ◽  
Bénédicte MOUSSON de CAMARET ◽  
Réjane BEUGNOT ◽  
Claire REMACLE ◽  
...  
Keyword(s):  
Complex I ◽  
Nadh Dehydrogenase ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Membrane Association ◽  
Oxidoreductase Activity ◽  
Mitochondrial Inner Membrane ◽  
The Matrix ◽  
Complex I Assembly ◽  
Human Complex

Mitochondria-encoded ND (NADH dehydrogenase) subunits, as components of the hydrophobic part of complex I, are essential for NADH:ubiquinone oxidoreductase activity. Mutations or lack of expression of these subunits have significant pathogenic consequences in humans. However, the way these events affect complex I assembly is poorly documented. To understand the effects of particular mutations in ND subunits on complex I assembly, we studied four human cell lines: ND4 non-expressing cells, ND5 non-expressing cells, and rho° cells that do not express any ND subunits, in comparison with normal complex I control cells. In control cells, all the seven analysed nuclear-encoded complex I subunits were found to be attached to the mitochondrial inner membrane, except for the 24 kDa subunit, which was nearly equally partitioned between the membranes and the matrix. Absence of a single ND subunit, or even all the seven ND subunits, caused no major changes in the nuclear-encoded complex I subunit content of mitochondria. However, in cells lacking ND4 or ND5, very low amounts of 24 kDa subunit were found associated with the membranes, whereas most of the other nuclear-encoded subunits remained attached. In contrast, membrane association of most of the nuclear subunits was significantly reduced in the absence of all seven ND proteins. Immunopurification detected several subcomplexes. One of these, containing the 23, 30 and 49 kDa subunits, also contained prohibitin. This is the first description of prohibitin interaction with complex I subunits and suggests that this protein might play a role in the assembly or degradation of mitochondrial complex I.

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