“Labile” heme critically regulates mitochondrial biogenesis through the transcriptional co-activator Hap4p in Saccharomyces cerevisiae

Heme (iron protoporphyrin IX) is a well-known prosthetic group for enzymes involved in metabolic pathways such as oxygen transport and electron transfer through the mitochondrial respiratory chain. However, heme has also been shown to be an important regulatory molecule (as “labile” heme) for divers...

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Published in:	The Journal of biological chemistry Vol. 295; no. 15; pp. 5095 - 5109
Main Authors:	Bouchez, Cyrielle L., Yoboue, Edgar D., de la Rosa Vargas, Livier E., Salin, Bénédicte, Cuvellier, Sylvain, Rigoulet, Michel, Duvezin-Caubet, Stéphane, Devin, Anne
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 10-04-2020 American Society for Biochemistry and Molecular Biology
Subjects:	Bioenergetics CCAAT-Binding Factor - genetics CCAAT-Binding Factor - metabolism gene regulation HAP complex Hap4p heme Hemin - metabolism labile heme mitochondria Mitochondria - metabolism mitochondrial biogenesis Organelle Biogenesis oxidation-reduction (redox) oxidative phosphorylation (OXPHOS) Oxygen Consumption Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae - metabolism Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Signal Transduction transcription factor yeast HAP complex transcription factor bioenergetics heme gene regulation mitochondria oxidation-reduction (redox) Hap4p labile heme mitochondrial biogenesis yeast oxidative phosphorylation (OXPHOS)
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Summary:	Heme (iron protoporphyrin IX) is a well-known prosthetic group for enzymes involved in metabolic pathways such as oxygen transport and electron transfer through the mitochondrial respiratory chain. However, heme has also been shown to be an important regulatory molecule (as “labile” heme) for diverse processes such as translation, kinase activity, and transcription in mammals, yeast, and bacteria. Taking advantage of a yeast strain deficient for heme production that enabled controlled modulation and monitoring of labile heme levels, here we investigated the role of labile heme in the regulation of mitochondrial biogenesis. This process is regulated by the HAP complex in yeast. Using several biochemical assays along with EM and epifluorescence microscopy, to the best of our knowledge, we show for the first time that cellular labile heme is critical for the post-translational regulation of HAP complex activity, most likely through the stability of the transcriptional co-activator Hap4p. Consequently, we found that labile heme regulates mitochondrial biogenesis and cell growth. The findings of our work highlight a new mechanism in the regulation of mitochondrial biogenesis by cellular metabolites.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Ruma Banerjee Both authors contributed equally to this work.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.RA120.012739