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Heme induces HAP4 transcription and mitochondrial respiration
Author(s) -
Zhang Tiantian,
Vancura Ales
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.756.6
Subject(s) - citric acid cycle , oxidative phosphorylation , heme , mitochondrion , biochemistry , transcription (linguistics) , biology , microbiology and biotechnology , transcription factor , saccharomyces cerevisiae , gene , metabolism , enzyme , linguistics , philosophy
Regulation of mitochondrial biogenesis and respiration is a complex process that involves several signaling pathways and transcription factors, as well as communication between the nuclear and mitochondrial genomes. We have shown previously that decreased expression of histones or a defect in nucleosome assembly in Saccharomyces cerevisiae result in increased mitochondrial DNA (mtDNA) copy number, oxygen consumption, ATP synthesis, and expression of genes encoding enzymes of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Transcription of genes involved in TCA cycle and OXPHOS induced by altered chromatin structure requires the activities of Hap1p and Hap2/3/4/5p complex as well as transport and metabolism of pyruvate in mitochondria. Here we show that this pyruvate‐derived metabolite is heme. Heme biosynthesis starts in mitochondria; it requires glycine and the TCA cycle intermediate succinyl‐CoA for synthesis of 5‐aminolevulinic acid (ALA), a key precursor for heme biosynthesis. Heme induces transcription of HAP4 , the transcriptional activation subunit of the Hap2/3/4/5p complex, in a Hap1p‐ and Hap2/3/4/5p‐dependent manner. Since the transcription of genes involved in TCA cycle and OXPHOS is repressed by glucose in yeast, heme levels are limiting for HAP4 transcription and the activity of the Hap2/3/4/5p complex. Increasing heme levels induces HAP4 transcription and mitochondrial respiration. Together, our data indicate that carbon flux into the TCA cycle regulates heme synthesis, which, in turn, regulates HAP4 transcription and mitochondrial respiration. Support or Funding Information NIH/National Institute of Gerneral Medical Science provided funding to Ales Vancura under grant number 1R15GM120710‐01