title: ISC1-dependent metabolic adaptation reveals an indispensable role for mitochondria in induction of nuclear genes during the diauxic shift in Saccharomyces cerevisiae.
abstract: Growth of Saccharomyces cerevisiae following glucose depletion (the diauxic shift) depends on a profound metabolic adaptation accompanied by a global reprogramming of gene expression. In this study, we provide evidence for a heretofore unsuspected role for Isc1p in mediating this reprogramming. Initial studies revealed that yeast cells deleted in ISC1, the gene encoding inositol sphingolipid phospholipase C, which resides in mitochondria in the post-diauxic phase, showed defective aerobic respiration in the post-diauxic phase but retained normal intrinsic mitochondrial functions, including intact mitochondrial DNA, normal oxygen consumption, and normal mitochondrial polarization. Microarray analysis revealed that the Deltaisc1 strain failed to up-regulate genes required for nonfermentable carbon source metabolism during the diauxic shift, thus suggesting a mechanism for the defective supply of respiratory substrates into mitochondria in the post-diauxic phase. This defect in regulating nuclear gene induction in response to a defect in a mitochondrial enzyme raised the possibility that mitochondria may initiate diauxic shift-associated regulation of nucleus-encoded genes. This was established by demonstrating that in respiratory-deficient petite cells these genes failed to be up-regulated across the diauxic shift in a manner similar to the Deltaisc1 strain. Isc1p- and mitochondrial function-dependent genes significantly overlapped with Adr1p-, Snf1p-, and Cat8p-dependent genes, suggesting some functional link among these factors. However, the retrograde response was not activated in Deltaisc1, suggesting that the response of Deltaisc1 cannot be simply attributed to mitochondrial dysfunction. These results suggest a novel role for Isc1p in allowing the reprogramming of gene expression during the transition from anaerobic to aerobic metabolism.
authors.affiliation: Biochemistry and Molecular Biology and Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitagaki
authors.forename: L Ashley
authors.initials: LA
authors.lastname: Cowart
authors.forename: Nabil
authors.initials: N
authors.lastname: Matmati
authors.forename: David
authors.initials: D
authors.lastname: Montefusco
authors.forename: Jason
authors.initials: J
authors.lastname: Gandy
authors.forename: Silvia Vaena
authors.initials: SV
authors.lastname: de Avalos
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Novgorodov
authors.forename: Jim
authors.initials: J
authors.lastname: Zheng
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002244:Carbon / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics*; D019069:Cell Respiration / Q000502:physiology; D003470:Culture Media / Q000737:chemistry; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction; D000431:Ethanol / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005947:Glucose / Q000378:metabolism; D046228:Microarray Analysis; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism*
chemical_list: D003470:Culture Media; D004272:DNA, Mitochondrial; D029701:Saccharomyces cerevisiae Proteins; D000431:Ethanol; D002244:Carbon; C509911:ADH2 protein, S cerevisiae; D000426:Alcohol Dehydrogenase; C419391:ISC1 protein, S cerevisiae; D010738:Type C Phospholipases; D005947:Glucose