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The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.

Publication ,  Journal Article
Acevedo, A; Jones, AE; Danna, BT; Turner, R; Montales, KP; Benincá, C; Reue, K; Shirihai, OS; Stiles, L; Wallace, M; Wang, Y; Bertholet, AM ...
Published in: J Biol Chem
March 2024

Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid) is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and branched-chain α-ketoacid levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here, we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show that BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly sixfold less potent than the prototypical uncoupler 2,4-dinitrophenol and phenocopies 2,4-dinitrophenol in lowering de novo lipogenesis and mitochondrial superoxide production. The data suggest that the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

March 2024

Volume

300

Issue

3

Start / End Page

105702

Location

United States

Related Subject Headings

  • Reactive Oxygen Species
  • Rats
  • Protein Kinase Inhibitors
  • Mitochondrial Membranes
  • Mice
  • Metabolic Diseases
  • Lipogenesis
  • Humans
  • Cells, Cultured
  • Cell Line
 

Citation

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Acevedo, A., Jones, A. E., Danna, B. T., Turner, R., Montales, K. P., Benincá, C., … Divakaruni, A. S. (2024). The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis. J Biol Chem, 300(3), 105702. https://doi.org/10.1016/j.jbc.2024.105702
Acevedo, Aracely, Anthony E. Jones, Bezawit T. Danna, Rory Turner, Katrina P. Montales, Cristiane Benincá, Karen Reue, et al. “The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.J Biol Chem 300, no. 3 (March 2024): 105702. https://doi.org/10.1016/j.jbc.2024.105702.
Acevedo A, Jones AE, Danna BT, Turner R, Montales KP, Benincá C, et al. The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis. J Biol Chem. 2024 Mar;300(3):105702.
Acevedo, Aracely, et al. “The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.J Biol Chem, vol. 300, no. 3, Mar. 2024, p. 105702. Pubmed, doi:10.1016/j.jbc.2024.105702.
Acevedo A, Jones AE, Danna BT, Turner R, Montales KP, Benincá C, Reue K, Shirihai OS, Stiles L, Wallace M, Wang Y, Bertholet AM, Divakaruni AS. The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis. J Biol Chem. 2024 Mar;300(3):105702.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

March 2024

Volume

300

Issue

3

Start / End Page

105702

Location

United States

Related Subject Headings

  • Reactive Oxygen Species
  • Rats
  • Protein Kinase Inhibitors
  • Mitochondrial Membranes
  • Mice
  • Metabolic Diseases
  • Lipogenesis
  • Humans
  • Cells, Cultured
  • Cell Line