Inhibition of hepatocytic autophagy by adenosine, adenosine analogs and AMP

A. Kovács, Paul B. Gordon, Else Marie Grotterød, Per O. Seglen

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Autophagy, measured in isolated rat hepatocytes as the sequestration of electroinjected [3H]raffinose, was moderately (17%) inhibited by adenosine (0.4 mM) alone, but more strongly (85%) in the presence of the adenosine deaminase inhibitor, 2'-deoxycoformycin (50 μM), suggesting that metabolic deamination of adenosine limited its inhibitory effectiveness. The adenosine analogs, 6-methylmercaptopurine riboside and N6,N6-dimethyladenosine, inhibited autophagy by 89% and 99%, respectively, at 0.5 mM, probably reflecting the adenosine deaminase-resistance of their 6-substitutions. 5-lodotubercidin (10 μM), an adenosine kinase inhibitor, blocked the conversion of adenosine to AMP and largely abolished the inhibitory effects of both adenosine and its analogs, indicating that AMP/nucleotide formation was required for inhibition of autophagy. Inhibition by adenosine of autophagic protein degradation, measured as the release of [14C]valine from prelabelled protein, was similarly potentiated by deoxycoformycin and prevented by iodotubercidin. Inhibition of autophagy by added AMP, ADP or ATP (0.3-1 mM) was, likewise, potentiated by deoxycoformycin and prevented by iodotubercidin, suggesting dephosphorylation to adenosine and intracellular re-phosphorylation to AMP. Suppression of autophagy by AMP may be regarded as a feedback inhibition of autophagic RNA degradation, or as an aspect of the general down-regulation of energy-requiring processes that occurs under conditions of ATP depletion, when AMP levels are high.

Original languageEnglish
Pages (from-to)1341-1347
Number of pages7
JournalBiological Chemistry
Volume379
Issue number11
Publication statusPublished - 1998

Fingerprint

Autophagy
Adenosine Monophosphate
Adenosine
Pentostatin
Methylthioinosine
Adenosine Triphosphate
Adenosine Deaminase Inhibitors
Adenosine Kinase
Raffinose
Degradation
Deamination
Phosphorylation
Adenosine Deaminase
RNA Stability
Valine
Adenosine Diphosphate
Proteolysis
Rats
Hepatocytes
Proteins

Keywords

  • 5-iodotubercidin
  • Deoxycoformycin
  • Dimethyladenosine
  • Hepatocyte
  • Liver
  • Methylmercaptopurine riboside

ASJC Scopus subject areas

  • Biochemistry

Cite this

Kovács, A., Gordon, P. B., Grotterød, E. M., & Seglen, P. O. (1998). Inhibition of hepatocytic autophagy by adenosine, adenosine analogs and AMP. Biological Chemistry, 379(11), 1341-1347.

Inhibition of hepatocytic autophagy by adenosine, adenosine analogs and AMP. / Kovács, A.; Gordon, Paul B.; Grotterød, Else Marie; Seglen, Per O.

In: Biological Chemistry, Vol. 379, No. 11, 1998, p. 1341-1347.

Research output: Contribution to journalArticle

Kovács, A, Gordon, PB, Grotterød, EM & Seglen, PO 1998, 'Inhibition of hepatocytic autophagy by adenosine, adenosine analogs and AMP', Biological Chemistry, vol. 379, no. 11, pp. 1341-1347.
Kovács, A. ; Gordon, Paul B. ; Grotterød, Else Marie ; Seglen, Per O. / Inhibition of hepatocytic autophagy by adenosine, adenosine analogs and AMP. In: Biological Chemistry. 1998 ; Vol. 379, No. 11. pp. 1341-1347.
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