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Degradation of the mitochondrial complex I assembly factor TMEM126B under chronic hypoxia

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Abstract

Cell stress such as hypoxia elicits adaptive responses, also on the level of mitochondria, and in part is mediated by the hypoxia-inducible factor (HIF) 1α. Adaptation of mitochondria towards acute hypoxic conditions is reasonably well understood, while regulatory mechanisms, especially of respiratory chain assembly factors, under chronic hypoxia remains elusive. One of these assembly factors is transmembrane protein 126B (TMEM126B). This protein is part of the mitochondrial complex I assembly machinery. We identified changes in complex I abundance under chronic hypoxia, in association with impaired substrate-specific mitochondrial respiration. Complexome profiling of isolated mitochondria of the human leukemia monocytic cell line THP-1 revealed HIF-1α-dependent deficits in complex I assembly and mitochondrial complex I assembly complex (MCIA) abundance. Of all mitochondrial MCIA members, we proved a selective HIF-1-dependent decrease of TMEM126B under chronic hypoxia. Mechanistically, HIF-1α induces the E3-ubiquitin ligase F-box/WD repeat-containing protein 1A (β-TrCP1), which in turn facilitates the proteolytic degradation of TMEM126B. Attenuating a functional complex I assembly appears critical for cellular adaptation towards chronic hypoxia and is linked to destruction of the mitochondrial assembly factor TMEM126B.

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Abbreviations

ACAD9:

Acyl-CoA dehydrogenase family member 9

ADP:

Adenosine diphosphate

Akt:

RAC-alpha serine/threonine-protein kinase

ATP:

Adenosine triphosphate

ATP5a:

ATP synthase subunit alpha

β-TrCP:

F-box/WD repeat-containing protein 1A

BNE:

Blue native electrophoresis

ChIP:

Chromatin immunoprecipitation

CHX:

Cycloheximide

COX:

Cytochrome c oxidase subunit

DMOG:

Dimethyloxalylglycine

DMSO:

Dimethyl sulfoxide

ECSIT:

Evolutionarily conserved signaling intermediate in toll pathway

ETF:

Electron transfer flavoprotein

FAD:

Flavin adenine dinucleotide

FCCP:

Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone

GFP:

Green fluorescent protein

GPDH:

Glycerol-3-phosphate dehydrogenase

GSK3:

Glycogen synthase kinase-3

HIF:

Hypoxia-inducible factor

HIGD:

Hypoxia-inducible gene

IP:

Immunoprecipitation

IPTG:

Isopropyl-β-d-thiogalactopyranoside

KCN:

Potassium cyanide

LC:

Lactacystin

MCIA:

Mitochondrial complex I assembly complex

NAD:

Nicotinamide adenine dinucleotide

ND:

NADH-ubiquinone oxidoreductase chain

NDUFA:

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit

NDUFAF1:

Complex I intermediate-associated protein 30

NDUFA4L2:

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2

NDUFB:

NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit

NDUFS:

NADH dehydrogenase [ubiquinone] iron–sulfur protein

OXPHOS:

Oxidative phosphorylation

PHD:

Prolyl hydroxylase

PI3K:

Phosphatidylinositol 3-kinase

rot:

Rotenone

shC:

Cells transduced with control short hairpin RNA

sh1:

Cells transduced with short hairpin RNA against HIF-1α

sh2:

Cells transduced with short hairpin RNA against HIF-2α

TIMMDC1:

Translocase of inner mitochondrial membrane domain-containing protein 1

TMEM126B:

Transmembrane protein 126B

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Acknowledgements

We thank Tanja Keppler for excellent technical assistance, Jana Meisterknecht for competent support with BNE and 2D-BNE/SDS gels, and Ilka Siebels for technical assistance in respiration measurements.

Funding

This work was supported by the Deutsche Forschungsgemeinschaft [SFB 815, project Z1 (I.W.) and project A8 (B.B.)].

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Authors and Affiliations

  1. Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Dominik C. Fuhrmann, Tobias Schmid, Nathalie Dehne & Bernhard Brüne

  2. Functional Proteomics, SFB 815 Core Unit, Goethe-University Frankfurt, Frankfurt, Germany

    Ilka Wittig

  3. Department of Anesthesiology, Intensive-Care Medicine and Pain Therapy, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany

    Stefan Dröse

  4. German Center for Cardiovascular Research (DZHK), Partner Site Rhein Main, Frankfurt, Germany

    Ilka Wittig

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  1. Dominik C. Fuhrmann
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  4. Tobias Schmid
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  5. Nathalie Dehne
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Contributions

DF performed and planed the experiments and wrote the paper. IW performed complexome profiling and participated on paper writing. SD performed respiratory measurements. TS gave his expertise concerning β-TrCP experiments ND discussed data and literature. BB performed data interpretation, wrote the paper, and designed the project.

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Correspondence to Bernhard Brüne.

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Fuhrmann, D.C., Wittig, I., Dröse, S. et al. Degradation of the mitochondrial complex I assembly factor TMEM126B under chronic hypoxia. Cell. Mol. Life Sci. 75, 3051–3067 (2018). https://doi.org/10.1007/s00018-018-2779-y

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