Mmf1p Couples Amino Acid Metabolism to Mitochondrial DNA Maintenance in <italic toggle="yes">Saccharomyces cerevisiae</italic>

ABSTRACT A variety of metabolic deficiencies and human diseases arise from the disruption of mitochondrial enzymes and/or loss of mitochondrial DNA. Mounting evidence shows that eukaryotes have conserved enzymes that prevent the accumulation of reactive metabolites that cause stress inside the mitoc...

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Autores principales:	Dustin C. Ernst, Diana M. Downs
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	2-aminoacrylate RidA enamine deaminase metabolite stress mitochondrial genome Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/48c5f6be144a45238f762b4b86c5ff36
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spelling	oai:doaj.org-article:48c5f6be144a45238f762b4b86c5ff362021-11-15T15:53:26ZMmf1p Couples Amino Acid Metabolism to Mitochondrial DNA Maintenance in <italic toggle="yes">Saccharomyces cerevisiae</italic>10.1128/mBio.00084-182150-7511https://doaj.org/article/48c5f6be144a45238f762b4b86c5ff362018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00084-18https://doaj.org/toc/2150-7511ABSTRACT A variety of metabolic deficiencies and human diseases arise from the disruption of mitochondrial enzymes and/or loss of mitochondrial DNA. Mounting evidence shows that eukaryotes have conserved enzymes that prevent the accumulation of reactive metabolites that cause stress inside the mitochondrion. 2-Aminoacrylate is a reactive enamine generated by pyridoxal 5′-phosphate-dependent α,β-eliminases as an obligatory intermediate in the breakdown of serine. In prokaryotes, members of the broadly conserved RidA family (PF14588) prevent metabolic stress by deaminating 2-aminoacrylate to pyruvate. Here, we demonstrate that unmanaged 2-aminoacrylate accumulation in Saccharomyces cerevisiae mitochondria causes transient metabolic stress and the irreversible loss of mitochondrial DNA. The RidA family protein Mmf1p deaminates 2-aminoacrylate, preempting metabolic stress and loss of the mitochondrial genome. Disruption of the mitochondrial pyridoxal 5′-phosphate-dependent serine dehydratases (Ilv1p and Cha1p) prevents 2-aminoacrylate formation, avoiding stress in the absence of Mmf1p. Furthermore, chelation of iron in the growth medium improves maintenance of the mitochondrial genome in yeast challenged with 2-aminoacrylate, suggesting that 2-aminoacrylate-dependent loss of mitochondrial DNA is influenced by disruption of iron homeostasis. Taken together, the data indicate that Mmf1p indirectly contributes to mitochondrial DNA maintenance by preventing 2-aminoacrylate stress derived from mitochondrial amino acid metabolism. IMPORTANCE Deleterious reactive metabolites are produced as a consequence of many intracellular biochemical transformations. Importantly, reactive metabolites that appear short-lived in vitro have the potential to persist within intracellular environments, leading to pervasive cell damage and diminished fitness. To overcome metabolite damage, organisms utilize enzymatic reactive-metabolite defense systems to rid the cell of deleterious metabolites. In this report, we describe the importance of the RidA/YER057c/UK114 enamine/imine deaminase family in preventing 2-aminoacrylate stress in yeast. Saccharomyces cerevisiae lacking the enamine/imine deaminase Mmf1p was shown to experience pleiotropic growth defects and fails to maintain its mitochondrial genome. Our results provide the first line of evidence that uncontrolled 2-aminoacrylate stress derived from mitochondrial serine metabolism can negatively impact mitochondrial DNA maintenance in eukaryotes.Dustin C. ErnstDiana M. DownsAmerican Society for Microbiologyarticle2-aminoacrylateRidAenamine deaminasemetabolite stressmitochondrial genomeMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	2-aminoacrylate RidA enamine deaminase metabolite stress mitochondrial genome Microbiology QR1-502
spellingShingle	2-aminoacrylate RidA enamine deaminase metabolite stress mitochondrial genome Microbiology QR1-502 Dustin C. Ernst Diana M. Downs Mmf1p Couples Amino Acid Metabolism to Mitochondrial DNA Maintenance in <italic toggle="yes">Saccharomyces cerevisiae</italic>
description	ABSTRACT A variety of metabolic deficiencies and human diseases arise from the disruption of mitochondrial enzymes and/or loss of mitochondrial DNA. Mounting evidence shows that eukaryotes have conserved enzymes that prevent the accumulation of reactive metabolites that cause stress inside the mitochondrion. 2-Aminoacrylate is a reactive enamine generated by pyridoxal 5′-phosphate-dependent α,β-eliminases as an obligatory intermediate in the breakdown of serine. In prokaryotes, members of the broadly conserved RidA family (PF14588) prevent metabolic stress by deaminating 2-aminoacrylate to pyruvate. Here, we demonstrate that unmanaged 2-aminoacrylate accumulation in Saccharomyces cerevisiae mitochondria causes transient metabolic stress and the irreversible loss of mitochondrial DNA. The RidA family protein Mmf1p deaminates 2-aminoacrylate, preempting metabolic stress and loss of the mitochondrial genome. Disruption of the mitochondrial pyridoxal 5′-phosphate-dependent serine dehydratases (Ilv1p and Cha1p) prevents 2-aminoacrylate formation, avoiding stress in the absence of Mmf1p. Furthermore, chelation of iron in the growth medium improves maintenance of the mitochondrial genome in yeast challenged with 2-aminoacrylate, suggesting that 2-aminoacrylate-dependent loss of mitochondrial DNA is influenced by disruption of iron homeostasis. Taken together, the data indicate that Mmf1p indirectly contributes to mitochondrial DNA maintenance by preventing 2-aminoacrylate stress derived from mitochondrial amino acid metabolism. IMPORTANCE Deleterious reactive metabolites are produced as a consequence of many intracellular biochemical transformations. Importantly, reactive metabolites that appear short-lived in vitro have the potential to persist within intracellular environments, leading to pervasive cell damage and diminished fitness. To overcome metabolite damage, organisms utilize enzymatic reactive-metabolite defense systems to rid the cell of deleterious metabolites. In this report, we describe the importance of the RidA/YER057c/UK114 enamine/imine deaminase family in preventing 2-aminoacrylate stress in yeast. Saccharomyces cerevisiae lacking the enamine/imine deaminase Mmf1p was shown to experience pleiotropic growth defects and fails to maintain its mitochondrial genome. Our results provide the first line of evidence that uncontrolled 2-aminoacrylate stress derived from mitochondrial serine metabolism can negatively impact mitochondrial DNA maintenance in eukaryotes.
format	article
author	Dustin C. Ernst Diana M. Downs
author_facet	Dustin C. Ernst Diana M. Downs
author_sort	Dustin C. Ernst
title	Mmf1p Couples Amino Acid Metabolism to Mitochondrial DNA Maintenance in <italic toggle="yes">Saccharomyces cerevisiae</italic>
title_short	Mmf1p Couples Amino Acid Metabolism to Mitochondrial DNA Maintenance in <italic toggle="yes">Saccharomyces cerevisiae</italic>
title_full	Mmf1p Couples Amino Acid Metabolism to Mitochondrial DNA Maintenance in <italic toggle="yes">Saccharomyces cerevisiae</italic>
title_fullStr	Mmf1p Couples Amino Acid Metabolism to Mitochondrial DNA Maintenance in <italic toggle="yes">Saccharomyces cerevisiae</italic>
title_full_unstemmed	Mmf1p Couples Amino Acid Metabolism to Mitochondrial DNA Maintenance in <italic toggle="yes">Saccharomyces cerevisiae</italic>
title_sort	mmf1p couples amino acid metabolism to mitochondrial dna maintenance in <italic toggle="yes">saccharomyces cerevisiae</italic>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/48c5f6be144a45238f762b4b86c5ff36
work_keys_str_mv	AT dustincernst mmf1pcouplesaminoacidmetabolismtomitochondrialdnamaintenanceinitalictoggleyessaccharomycescerevisiaeitalic AT dianamdowns mmf1pcouplesaminoacidmetabolismtomitochondrialdnamaintenanceinitalictoggleyessaccharomycescerevisiaeitalic
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Mmf1p Couples Amino Acid Metabolism to Mitochondrial DNA Maintenance in <italic toggle="yes">Saccharomyces cerevisiae</italic>

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