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Abstract
The essential vitamin biotin is a covalent and tenaciously attached prosthetic group in several carboxylases that play important roles in the regulation of energy metabolism. Here we describe increased acetyl-CoA levels and mitochondrial hyperacetylation as downstream metabolic effects of biotin deficiency. Upregulated mitochondrial acetylation sites correlate with the cellular deficiency of the Hst4p deacetylase, and a biotin-starvation-induced accumulation of Hst4p in mitochondria supports a role for Hst4p in lowering mitochondrial acetylation. We show that biotin starvation and knockout of Hst4p cause alterations in cellular respiration and an increase in reactive oxygen species (ROS). These results suggest that Hst4p plays a pivotal role in biotin metabolism and cellular energy homeostasis, and supports that Hst4p is a functional yeast homologue of the sirtuin deacetylase SIRT3. With biotin deficiency being involved in various metabolic disorders, this study provides valuable insight into the metabolic effects biotin exerts on eukaryotic cells.
Highlights
The essential vitamin biotin is a covalent and tenaciously attached prosthetic group in several carboxylases that play important roles in the regulation of energy metabolism
Our results demonstrate that biotin deficiency manifests itself into mitochondrial hyperacetylation, and our large-scale proteomic data revealed that upregulated mitochondrial acetylation sites correlate with the cellular deficiency of the Hst4p deacetylase
To measure the cellular response to biotin availability, we metabolically labelled all proteins using stable isotope labelling of amino acids in cell culture (SILAC)[17]. Using this set-up we determined the cellular response of biotin, proteome and acetylome in cells exposed to normal amounts of biotin against those exposed to 100-fold excess, or complete depletion by quantitative mass spectrometry (MS) (Fig. 1a)
Summary
The essential vitamin biotin is a covalent and tenaciously attached prosthetic group in several carboxylases that play important roles in the regulation of energy metabolism. We show that biotin starvation and knockout of Hst4p cause alterations in cellular respiration and an increase in reactive oxygen species (ROS) These results suggest that Hst4p plays a pivotal role in biotin metabolism and cellular energy homeostasis, and supports that Hst4p is a functional yeast homologue of the sirtuin deacetylase SIRT3. Proteins engage in a wide array of cellular events where the specificity of the interactions is largely determined by their primary amino-acid sequence This can be heavily influenced by the presence of B200 different types of posttranslational modifications (PTMs)[1]. Contrary to such dynamic modifications, there are some PTMs with tenacious attachment and high specificity One such example is the essential vitamin biotin, which functions as a covalently linked prosthetic group in a handful of key metabolic enzymes[3]. To investigate this in more detail, we selected S. cerevisiae as a model organism since the internal biotin pool can be directly manipulated from the growth media[16]
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