Subunit-specific Incorporation Efficiency and Kinetics in Mitochondrial Complex I Homeostasis

Dieteren, Cindy E.; Koopman, Werner J.H.; Swarts, H.G.P.; Peters, Janny G. P.; Maczuga, Piotr; Gemst, Jasper J. van; Masereeuw, Rosalinde; Smeitink, Jan A.M.; Nijtmans, Leo; Willems, Peter H.G.M.

doi:10.1074/jbc.m112.391151

Cited by 39 publications

(44 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The long delay in complex I restoration upon de-repression of INDH (Figure 6) is also indicative of a translation defect. In human cell lines, reassembly of complex I upon expression of a missing structural subunit took less than 24 h (Dieteren et al, 2012), whereas reassembly after transient inhibition of mitochondrial translation took 2 to 4 d (Ugalde et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

et al. 2013

View full text Add to dashboard Cite

The assembly of respiratory complexes is a multistep process, requiring coordinate expression of mitochondrial and nuclear genes and cofactor biosynthesis. We functionally characterized the iron-sulfur protein required for NADH dehydrogenase (INDH) in the model plant Arabidopsis thaliana. An indh knockout mutant lacked complex I but had low levels of a 650-kD assembly intermediate, similar to mutations in the homologous NUBPL (nucleotide binding protein-like) in Homo sapiens. However, heterozygous indh/+ mutants displayed unusual phenotypes during gametogenesis and resembled mutants in mitochondrial translation more than mutants in complex I. Gradually increased expression of INDH in indh knockout plants revealed a significant delay in reassembly of complex I, suggesting an indirect role for INDH in the assembly process. Depletion of INDH protein was associated with decreased 35 S-Met labeling of translation products in isolated mitochondria, whereas the steady state levels of several mitochondrial transcripts were increased. Mitochondrially encoded proteins were differentially affected, with near normal levels of cytochrome c oxidase subunit2 and Nad7 but little Nad6 protein in the indh mutant. These data suggest that INDH has a primary role in mitochondrial translation that underlies its role in complex I assembly.

show abstract

Section: Discussionmentioning

confidence: 99%

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

et al. 2013

View full text Add to dashboard Cite

show abstract

“…An independently formed membrane arm subcomplex containing MT-ND2, MT-ND3, MT-ND6, and NDUFB6 (ϳ0.5 MDa) then assembles with the ϳ0.4-MDa complex to generate an ϳ0.8-MDa intermediate (10,11). Subsequently, components of the N module, including NDUFV1, NDUFV2, NDUFV3, NDUFS1, NDUFS4, NDUFS6, and NDUFA12, are added (11,39,40). The assembly factors are thought to remain associated with the various intermediates until the final step, where they dissociate to yield functional CI (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Guarani

Paulo

Zhai

et al. 2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

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.

show abstract

“…Complex I biogenesis is thus a concerted process in which intramitochondrial expression of the mtDNA-encoded subunits is coordinated with extramitochondrial expression of the nuclear DNA-encoded subunits, their import and maturation in mitochondria, where, in a stepwise process, a copy of each subunit is assembled in the mature complex [5]. In addition to "de novo" biogenesis of the entire complex, nuclear encoded subunits, belonging to the matrix exposed catalytic moiety of the complex, undergo a relatively rapid turnover, with exchange of preexisting with newly synthesized copies [6,7]. This exchange contributes to replace "aged", oxidatively damaged, subunits in the complex with new ones, thus preserving its functional activity [8].…”

Section: Introductionmentioning

confidence: 99%

Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain

Rasmo¹,

Signorile²,

Santeramo³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

In mammalian cells the nuclear-encoded subunits of complex I are imported into mitochondria, where they are assembled with mt-DNA encoded subunits in the complex, or exchanged with pre-existing copies in the complex. The present work shows that in fibroblast cultures inhibition by KH7 of cAMP production in the mitochondrial matrix by soluble adenylyl cyclase (sAC) results in decreased amounts of free non-incorporated nuclear-encoded NDUFS4, NDUFV2 and NDUFA9 subunits of the catalytic moiety and inhibition of the activity of complex I. Addition of permeant 8-Br-cAMP prevents this effect of KH7. KH7 inhibits accumulation in isolated rat-liver mitochondria and incorporation in complex I of "in vitro" produced, radiolabeled NDUFS4 and NDUFV2 subunits. 8-Br-cAMP prevents also this effect of KH7. Use of protease inhibitors shows that intramitochondrial cAMP exerts this positive effect on complex I by preventing digestion of nuclear-encoded subunits by mitochondrial protease(s), whose activity is promoted by KH7 and H89, an inhibitor of PKA.

show abstract

Subunit-specific Incorporation Efficiency and Kinetics in Mitochondrial Complex I Homeostasis

Cited by 39 publications

References 32 publications

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

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

Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain

Contact Info

Product

Resources

About