ISC1-dependent Metabolic Adaptation Reveals an Indispensable Role for Mitochondria in Induction of Nuclear Genes during the Diauxic Shift in Saccharomyces cerevisiae

• Published in: The Journal of biological chemistry 2009-04, Vol.284 (16), p.10818-10830
• Main Authors: Kitagaki, Hiroshi, Cowart, L. Ashley, Matmati, Nabil, Montefusco, David, Gandy, Jason, de Avalos, Silvia Vaena, Novgorodov, Sergei A., Zheng, Jim, Obeid, Lina M., Hannun, Yusuf A.
• Format: Article
• Language: English
• Subjects: Alcohol Dehydrogenase - genetics; Alcohol Dehydrogenase - metabolism; Animals; Carbon - metabolism; Cell Nucleus - genetics; Cell Respiration - physiology; Culture Media - chemistry; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Enzyme Induction; Ethanol - metabolism; Gene Expression Regulation, Fungal; Glucose - metabolism; Metabolism and Bioenergetics; Microarray Analysis; Mitochondria - metabolism; Molecular Sequence Data; Saccharomyces cerevisiae; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae - physiology; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Type C Phospholipases - genetics; Type C Phospholipases - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M805029200

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 Δisc1 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 Δisc1 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 Δisc1, suggesting that the response of Δisc1 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.