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

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 b-oxidation flux by labeled palmitate demonstrates that tBid inhibits b-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 palmitoyltransferase-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. Overexpression of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid on b-oxidation. The unexpected role of tBid in the regulation of lipid b-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.

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

“…Nevertheless, the synergism between orlistat (which does not promote ceramide or palmitate accumulation) and ABT-737 or Nutlin 3a motivates us to contemplate the possibility that fatty acid entry and/or FAO in mitochondria may ipso facto be involved in the regulation of the Bcl-2 apoptotic rheostat in leukemia cells. This last notion is supported by the previous observations that CPT-1 interacts with t-Bid (16) and with Bcl-2 (17), although the contributions of CPT-1 activity to t-Bid-induced apoptosis remain to be determined. Additional experiments will be required to address the significance of these interactions in the activation of the MPTP.…”

“…Furthermore, the truncated form of the proapoptotic Bcl-2 family member Bid (t-Bid) directly inhibits CPT1 activity, an effect antagonized by Bcl-2 overexpression (16), and CPT1 has been reported to associate with Bcl-2 (17), suggesting that the entry of fatty acids into the mitochondria may be directly linked to the Bcl-2 apoptotic rheostat. Notably, we have recently described that antagonism of Bcl-2 using ABT-737, a BH3 mimetic that disrupts the sequestration of Bax, Bak, and other proapoptotic Bcl-2 proteins by antiapoptotic Bcl-2 family members, induces apoptosis in leukemia cell lines and primary samples (18).…”

Regulation of mitochondrial ceramide distribution by members of the BCL-2 family

“…Several BCL-2 proteins affect cellular metabolism, including glucose and fatty acid metabolism (46)(47)(48), calcium homeostasis ( 49 ), and insulin secretion ( 50 ). Similar to these fi ndings, our data demonstrate a novel metabolic function for BAX and BAK in the regulation of endogenous ceramides.…”

Mitochondria as therapeutic targets for cancer chemotherapy

“…One study indicates that t-Bidmediated permeabilization occurs in a two-step process, the first step (CsA-independent) leading to a partial (B15%) cyt c release, and the second step (CsAsensitive) causing the total cyt c release and remodeling of the mitochondrial ultrastructure . t-Bid-mediated MOMP has also been reported to involve obligatory interactions with carnitine palmitoyl transferase 1 (Giordano et al, 2005) or mitochondrial carrier homolog 2 (Grinberg et al, 2005). Other proapoptotic proteins from the Bcl-2 family such as Bcl-2 antagonist of cell death (Bad), Bcl-2-interacting mediator of cell death (Bim), and Noxa are believed to induce apoptosis via an interaction with either Bax or Bak and/or by generating stable complexes with antiapoptotic Bcl-2/Bcl-X L (Adams, 2003).…”