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Multiple acyl-coA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection

ABSTRACT:

The human pathogen Mycobacterium tuberculosis (Mtb) devotes a significant fraction of its genome to fatty acid metabolism. Although Mtb depends on host fatty acids as a carbon source, fatty acid b-oxidation is mediated by genetically redundant enzymes, which has hampered the development of antitubercular drugs targeting this metabolic pathway. Here, we identify rv0338c, referred to as etfDMtb, to encode a membrane dehydrogenase essential for fatty acid b-oxidation in Mtb. An etfD deletion mutant (DetfD) was incapable of growing on fatty acids in vitro, with long-chain fatty acids being bactericidal, and failed to grow and survive in mice. The DetfD metabolome revealed a block in b-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs). In many organisms, including humans, ACADs are functionally dependent on an electron transfer flavoprotein (ETF) and cognate dehydrogenase. Immunoprecipitation identified EtfD in complex with FixA (EtfBMtb). FixA (EtfBMtb) and FixB (EtfAMtb) are homologous to the human ETF subunits. Our results demonstrate that EtfBAMtb constitutes Mtb’s ETF, while EtfDMtb, although not homologous to human EtfD, functions as the dehydrogenase. These findings identify Mtb’s fatty acid b-oxidation as a novel potential target for TB drug development.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase

SUBMITTER: Robert Jansen

PROVIDER: MTBLS2374 | MetaboLights | 2021-09-29

REPOSITORIES: MetaboLights

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Project description:How signals from fatty acid metabolism are translated into changes in food intake remains unclear. Previously we reported that mice with a genetic inactivation of Acads (short-chain acyl-CoA dehydrogenase), encoding the enzyme responsible for mitochondrial beta-oxidation of C4-C6 short-chain fatty acids (SCFAs), shift consumption away from fat and toward carbohydrate when offered a choice. This finding demonstrated that the loss of a specific enzyme in fatty acid oxidation alters the choice of diet intake. To our knowledge, there are no reports of studies on the effects of dietary fat on the brain transcriptome in genetic models of fatty acid oxidation deficiency. The current study aimed to identify molecular mediators underlying the effects of SCFA oxidation deficiency on food intake. The current study aimed to identify molecular mediators underlying the effects of SCFA oxidation deficiency on food intake. We performed a transcriptional screen for gene expression in brain tissue of Acads-/- and Acads+/+ mice fed either high-fat (HF) or low-fat (LF) diet for 2 d. Ingenuity Pathway Analysis revealed three top-scoring pathways significantly modified by genotype or diet: oxidative phosphorylation, mitochondrial dysfunction, and CREB signaling in neurons. A comparison of statistically significant responses in HF Acads-/- vs. HF Acads+/+ (3917) and Acads+/+ HF vs. LF Acads+/+ (3879) revealed 2551 genes or approximately 65% in common between the two experimental comparisons. All but one of these genes were expressed in opposite direction with similar magnitude, demonstrating that Acads-deficient mice fed HF diet display transcriptional responses that mimic those of wildtype Acads+/+ mice fed LF diet. Intriguingly, genes involved in energy sensing and metabolism followed this pattern. Quantitative RT-PCR in hypothalamus confirmed the dysregulation of several genes in these pathways. Western blotting showed that the combination of Acads deficiency and HF diet increased hypothalamic AMP-kinase, a key protein in an energy-sensing cascade that responds to depletion of ATP. Our results suggest that the decreased beta oxidation of short-chain fatty acids in Acads-deficient mice fed HF diet produces a state of energy deficiency in the brain and that AMP-kinase is the cellular energy-sensing mechanism linking fatty acid oxidation to feeding behavior in this model.

			Action	DRS
	MTBLS2374	Other
	FILES	Other
	a_MTBLS2374_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	files-all.json	Other
	i_Investigation.txt	Txt

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Multiple acyl-coA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection

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