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FAD-dependent regulation of transcription, translation, post-translational processing, and post-processing stability of various mitochondrial acyl-CoA dehydrogenases and of electron transfer flavoprotein and the site of holoenzyme formation.

Abstract
The most prominent biochemical consequence of riboflavin deficiency in rats is a drastic decrease in various acyl-CoA dehydrogenase activities, especially that of short chain and isovaleryl-CoA dehydrogenase (IVD). As a result, oxidation of fatty acids and leucine is severely inhibited. We studied the effects of FAD at various stages of acyl-CoA dehydrogenase biogenesis. Immunoblot revealed severe losses of various acyl-CoA dehydrogenases and electron transfer flavoprotein in riboflavin-deficient rat liver mitochondria. The decreases in IVD and short chain acyl-CoA dehydrogenase were particularly severe, reaching values of 17 and 34% of controls, respectively. With the exception of IVD, the rate of in vitro transcription of the respective genes and the amounts of mRNAs of these flavoproteins in tissues increased 3-8.5-fold over controls. The amount of IVD mRNA and its transcription rate remained unchanged, suggesting that IVD expression is regulated separately from other acyl-CoA dehydrogenases. When riboflavin was depleted, in vitro translation of acyl-CoA dehydrogenase and electron transfer flavoprotein alpha-subunit mRNAs was moderately inhibited. Translation of non-flavoproteins was also inhibited. The stability of precursor acyl-CoA dehydrogenases and their mitochondrial import/processing were unaffected. However, mature acyl-CoA dehydrogenases degraded markedly faster in deficient mitochondria than in controls. Regardless of whether precursors were translated under riboflavin-depleted or riboflavin replete conditions, mature acyl-CoA dehydrogenases survived well when imported into normal mitochondria but degraded faster when imported into deficient mitochondria. These findings indicate that FAD ligand binds to mature acyl-CoA dehydrogenase inside the mitochondria.
AuthorsM Nagao, K Tanaka
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 267 Issue 25 Pg. 17925-32 (Sep 05 1992) ISSN: 0021-9258 [Print] United States
PMID1517228 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Electron-Transferring Flavoproteins
  • Flavoproteins
  • RNA, Messenger
  • Flavin-Adenine Dinucleotide
  • Oxidoreductases
  • Acyl-CoA Dehydrogenases
  • Oxidoreductases Acting on CH-CH Group Donors
  • Isovaleryl-CoA Dehydrogenase
  • Ornithine Carbamoyltransferase
Topics
  • Acyl-CoA Dehydrogenases (biosynthesis, genetics, metabolism)
  • Animals
  • Electron-Transferring Flavoproteins
  • Flavin-Adenine Dinucleotide (metabolism, pharmacology)
  • Flavoproteins (biosynthesis, genetics, metabolism)
  • Gene Expression Regulation (drug effects)
  • Gene Expression Regulation, Enzymologic (drug effects)
  • Isovaleryl-CoA Dehydrogenase
  • Kinetics
  • Male
  • Mitochondria, Liver (drug effects, enzymology, metabolism)
  • Ornithine Carbamoyltransferase (biosynthesis, genetics)
  • Oxidoreductases (genetics, metabolism)
  • Oxidoreductases Acting on CH-CH Group Donors
  • Protein Biosynthesis (drug effects)
  • Protein Processing, Post-Translational (drug effects)
  • RNA, Messenger (metabolism)
  • Rats
  • Rats, Inbred Strains
  • Reticulocytes (drug effects, metabolism)
  • Riboflavin Deficiency (enzymology)
  • Time Factors
  • Transcription, Genetic (drug effects)

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