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Mitochondrial Energy Metabolism: Kgd4 is a novel subunit of the α-ketoglutarate dehydrogenase complex
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Mitochondria are essential organelles of eukaryotic cells and are responsible for their energy metabolism. The citric acid cycle, a chain of redox reactions in the mitochondrial matrix, is a central metabolic hub. The energy of these redox reactions is preserved in reducing equivalents, which are fed into the electron transport chain of the inner mitochondrial membrane. This process ultimately produces ATP.

Mitochondrial ribosomes are responsible for the synthesis of the hydrophobic core components of the respiratory chain complexes. Using the baker’s yeast Saccharomyces cerevisiae as a eukaryotic model organism, the composition of the polypeptide tunnel exit of mitochondrial ribosomes was defined. We identified novel mitochondria-specific ribosomal proteins and generated insights into how they contribute to the specialization of mitochondrial ribosomes.

In a second approach, Kgd4 was identified as a novel structural component of the a-ketoglutarate dehydrogenase complex (KGDH), which is part of the citric acid cycle. We demonstrate that this protein is responsible for recruiting one essential subunit to the catalytic core of the complex. By ensuring the structural integrity, Kgd4 indirectly maintains the catalytic function of the enzyme complex. Kgd4 also represents a rare exception from the standard protein synthesis process. There are two isofroms of the protein, which differ in the length of the amino acid sequence. Both Kgd4 forms contribute to KGDH stability and activity. Translation of the long isoform starts from a non-canonical UUG codon upstream of the commonly used start-codon AUG. This provides insights into the flexibility of translation initiation in yeast. Finally, we purified the fully intact and functional KGDH complex from isolated yeast mitochondria for future structural studies. These experiments also revealed details about the interaction of the complex with the inner mitochondrial membrane.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Biochemistry and Biophysics, Stockholm University , 2014. , s. 60
Nyckelord [en]
Mitochondria, α-ketoglutarate dehydrogenase, Kgd4, Krebs cycle
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
biokemi
Identifikatorer
URN: urn:nbn:se:su:diva-106696ISBN: 978-91-7447-958-4 (tryckt)OAI: oai:DiVA.org:su-106696DiVA, id: diva2:738185
Disputation
2014-09-30, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript. Paper 4: Manuscript.

Tillgänglig från: 2014-09-08 Skapad: 2014-08-15 Senast uppdaterad: 2014-09-15Bibliografiskt granskad
Delarbeten
1. Proteins at the Polypeptide Tunnel Exit of the Yeast Mitochondrial Ribosome
Öppna denna publikation i ny flik eller fönster >>Proteins at the Polypeptide Tunnel Exit of the Yeast Mitochondrial Ribosome
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2010 (Engelska)Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, nr 25, s. 19022-19028Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Oxidative phosphorylation in mitochondria requires the synthesis of proteins encoded in the mitochondrial DNA. The mitochondrial translation machinery differs significantly from that of the bacterial ancestor of the organelle. This is especially evident from many mitochondria-specific ribosomal proteins. An important site of the ribosome is the polypeptide tunnel exit. Here, nascent chains are exposed to an aqueous environment for the first time. Many biogenesis factors interact with the tunnel exit of pro- and eukaryotic ribosomes to help the newly synthesized proteins to mature. To date, nothing is known about the organization of the tunnel exit of mitochondrial ribosomes. We therefore undertook a comprehensive approach to determine the composition of the yeast mitochondrial ribosomal tunnel exit. Mitochondria contain homologues of the ribosomal proteins located at this site in bacterial ribosomes. Here, we identified proteins located in their proximity by chemical cross-linking and mass spectrometry. Our analysis revealed a complex network of interacting proteins including proteins and protein domains specific to mitochondrial ribosomes. This network includes Mba1, the membrane-bound ribosome receptor of the inner membrane, as well as Mrpl3, Mrpl13, and Mrpl27, which constitute ribosomal proteins exclusively found in mitochondria. This unique architecture of the tunnel exit is presumably an adaptation of the translation system to the specific requirements of the organelle.

Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:su:diva-81044 (URN)10.1074/jbc.M110.113837 (DOI)000278727800010 ()
Tillgänglig från: 2012-10-08 Skapad: 2012-10-08 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
2. The novel component Kgd4 recruits the E3 subunit to the mitochondrial α-ketoglutarate dehydrogenase
Öppna denna publikation i ny flik eller fönster >>The novel component Kgd4 recruits the E3 subunit to the mitochondrial α-ketoglutarate dehydrogenase
Visa övriga...
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:su:diva-106693 (URN)
Tillgänglig från: 2014-08-15 Skapad: 2014-08-15 Senast uppdaterad: 2014-08-18
3. Alternative initiation at a UUG codon gives rise to two functional variants of the mitochondrial protein Kgd4
Öppna denna publikation i ny flik eller fönster >>Alternative initiation at a UUG codon gives rise to two functional variants of the mitochondrial protein Kgd4
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:su:diva-106694 (URN)
Tillgänglig från: 2014-08-15 Skapad: 2014-08-15 Senast uppdaterad: 2014-08-18
4. KGDH membrane association, purification and structure
Öppna denna publikation i ny flik eller fönster >>KGDH membrane association, purification and structure
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:su:diva-106695 (URN)
Tillgänglig från: 2014-08-15 Skapad: 2014-08-15 Senast uppdaterad: 2014-08-18

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