tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1

A. Giordano, M. Calvani, O. Petillo, P. Grippo, F. Tuccillo, M. A B Melone, P. Bonelli, A. Calarco, G. Peluso

Research output: Contribution to journalArticle

Abstract

Recent studies suggest a close relationship between cell metabolism and apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated with truncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. The measurement of β-oxidation flux by labeled palmitate demonstrates that tBld inhibits β-oxidation, thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitine and acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyl-transferase-1 (CPT-1). We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease. Overexpmssion of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBld on β-oxidation. The unexpected role of tBid in the regulation of lipid β-oxidation suggests a model in which tBid-induced metabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which might become participants in the apoptotic pathway.

Original languageEnglish
Pages (from-to)603-613
Number of pages11
JournalCell Death and Differentiation
Volume12
Issue number6
DOIs
Publication statusPublished - Jun 2005

Keywords

  • β-oxidation
  • CPT-1
  • Malonyl-CoA
  • Mitochondria
  • tBID

ASJC Scopus subject areas

  • Cell Biology

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