Mitochondrial retrograde signaling mediates communication from altered mitochondria to the nucleus and is involved in many normal and pathophysiological changes, including cell metabolic reprogramming linked to cancer development and progression in mammals. The major mitochondrial retrograde pathway described in yeast includes three activators, Rtg1p, Rtg2p and Rtg3p, and repressors, Mks1p and Bmh1p/Bmh2p. Using differentiated yeast colonies, we show that Mks1p-Rtg pathway regulation is complex and includes three branches that divergently regulate the properties and fate of three specifically localized cell subpopulations via signals from differently altered mitochondria. The newly identified RTG pathway-regulated genes ATO1/ATO2 are expressed in colonial upper (U) cells, the cells with active TORC1 that metabolically resemble tumor cells, while CIT2 is a typical target induced in one subpopulation of starving lower (L) cells. The viability of the second L cell subpopulation is strictly dependent on RTG signaling. Additional co-activators of Rtg1p-Rtg3p specific to particular gene targets of each branch are required to regulate cell differentiation.

Department of Genetics and Microbiology Faculty of Science Charles University Prague Prague Czech Republic

Institute of Microbiology of the CAS v v i Prague Czech Republic

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Jazwinski SM. The Retrograde Response: A Conserved Compensatory Reaction to Damage from Within and from Without. Prog Mol Biol Transl. 2014;127:133–154. PubMed PMC

Amuthan G, Biswas G, Zhang SY, Klein-Szanto A, Vijayasarathy C, Avadhani NG. Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. Embo J. 2001;20:1910–1920. PubMed PMC

Miceli MV, Jiang JC, Tiwari A, Rodriguez-Quinones JF, Jazwinski SM. Loss of mitochondrial membrane potential triggers the retrograde response extending yeast replicative lifespan. Front Genet. 2011;2:102. PubMed PMC

Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012;12:685–698. PubMed PMC

Guha M, Avadhani NG. Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics. Mitochondrion. 2013;13:577–591. PubMed PMC

Biswas G, Tang W, Sondheimer N, Guha M, Bansal S, Avadhani NG. A distinctive physiological role for I kappa B beta in the propagation of mitochondrial respiratory stress signaling. J Biol Chem. 2008;283:12586–12594. PubMed PMC

Sekito T, Thornton J, Butow RA. Mitochondria-to-nuclear signaling is regulated by the subcellular localization of the transcription factors Rtg1p and Rtg3p. Mol Biol Cell. 2000;11:2103–2115. PubMed PMC

Ferreira JR, Spirek M, Liu ZC, Butow RA. Interaction between Rtg2p and Mks1p in the regulation of the RTG pathway of Saccharomyces cerevisiae. Gene. 2005;354:2–8. PubMed

Liu ZC, Sekito T, Spirek M, Thornton J, Butow RA. Retrograde signaling is regulated by the dynamic interaction between Rtg2p and Mks1p. Mol Cell. 2003;12:401–411. PubMed

Dilova I, Aronova S, Chen JCY, Powers T. Tor signaling and nutrient-based signals converge on Mks1p phosphorylation to regulate expression of Rtg1p center dot Rtg3p-dependent target genes. J Biol Chem. 2004;279:46527–46535. PubMed

Dilova I, Chen CY, Powers T. Mks1 in concert with TOR signaling negatively regulates RTG target gene expression in S. cerevisiae. Curr Biol. 2002;12:389–395. PubMed

Liu ZC, Butow RA. Mitochondrial retrograde signaling. Annu Rev Genet. 2006;40:159–185. PubMed

Butow RA, Avadhani NG. Mitochondrial signaling: The retrograde response. Mol Cell. 2004;14:1–15. PubMed

Hallstrom TC, Moye-Rowley WS. Multiple signals from dysfunctional mitochondria activate the pleiotropic drug resistance pathway in Saccharomyces cerevisiae. J Biol Chem. 2000;275:37347–37356. PubMed

Srinivasan V, Kriete A, Sacan A, Jazwinski SM. Comparing the yeast retrograde response and NF-kappa B stress responses: implications for aging. Aging Cell. 2010;9:933–941. PubMed PMC

Jazwinski SM. The retrograde response: When mitochondrial quality control is not enough. BBA-Mol Cell Res. 2013;1833:400–409. PubMed PMC

DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Nat Acad Sci. 2007;104:19345–19350. PubMed PMC

Chelstowska A, Butow RA. Rtg genes in yeast that function in communication between mitochondria and the nucleus are also required for expression of genes encoding peroxisomal proteins. J Biol Chem. 1995;270:18141–18146. PubMed

Palkova Z, Wilkinson D, Vachova L. Aging and differentiation in yeast populations: elders with different properties and functions. FEMS Yeast Res. 2014;14:96–108. PubMed

Palkova Z, Devaux F, Ricicova M, Minarikova L, Le Crom S, Jacq C. Ammonia pulses and metabolic oscillations guide yeast colony development. Mol Biol Cell. 2002;13:3901–3914. PubMed PMC

Palkova Z, Janderova B, Gabriel J, Zikanova B, Pospisek M, Forstova J. Ammonia mediates communication between yeast colonies. Nature. 1997;390:532–536. PubMed

Vachova L, Hatakova L, Cap M, Pokorna M, Palkova Z. Rapidly developing yeast microcolonies differentiate in a similar way to aging giant colonies. Oxid Med Cell Longev. 2013;2013:102485. PubMed PMC

Vachova L, Devaux F, Kucerova H, Ricicova M, Jacq C, Palkova Z. Sok2p transcription factor is involved in adaptive program relevant for long term survival of Saccharomyces cerevisiae colonies. J Biol Chem. 2004;279:37973–37981. PubMed

Vachova L, Palkova Z. Physiological regulation of yeast cell death in multicellular colonies is triggered by ammonia. J Cell Biol. 2005;169:711–717. PubMed PMC

Cap M, Stepanek L, Harant K, Vachova L, Palkova Z. Cell differentiation within a yeast colony: Metabolic and regulatory parallels with a tumor-affected organism. Mol Cell. 2012;46:436–448. PubMed

Vachova L, Cap M, Palkova Z. Yeast colonies: a model for studies of aging, environmental adaptation, and longevity. Oxid Med Cell Longev. 2012;2012:601836. PubMed PMC

DeBerardinis RJ, Cheng T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29:313–324. PubMed PMC

Bruckmann A, Hensbergen PJ, Balog CIA, Deelder AM, Steensma HY, van Heusden GPH. Post-transcriptional Control of the Saccharomyces cerevisiae proteome by 14-3-3 proteins. J Proteome Res. 2007;6:1689–1699. PubMed

Vanheusden GPH, Griffiths DJF, Ford JC, Chinawoeng TFC, Schrader PAT, Carr AM, Steensma HY. The 14-3-3-proteins encoded by the Bmh1 and Bmh2 genes are essential in the yeast Saccharomyces cerevisiae and can be replaced by a plant homolog. Eur J Biochem. 1995;229:45–53. PubMed

Vachova L, Chernyavskiy O, Strachotova D, Bianchini P, Burdikova Z, Fercikova I, Kubinova L, Palkova Z. Architecture of developing multicellular yeast colony: spatio-temporal expression of Ato1p ammonium exporter. Environ Microbiol. 2009;11:1866–1877. PubMed

Ricicova M, Kucerova H, Vachova L, Palkova Z. Association of putative ammonium exporters Ato with detergent-resistant compartments of plasma membrane during yeast colony development: pH affects Ato1p localisation in patches. BBA-Biomembranes. 2007;1768:1170–1178. PubMed

Vachova L, Kucerova H, Devaux F, Ulehlova M, Palkova Z. Metabolic diversification of cells during the development of yeast colonies. Environ Microbiol. 2009;11(2):494–504. PubMed

Guaragnella N, Butow RA. ATO3 encoding a putative outward ammonium transporter is an RTG-independent retrograde responsive gene regulated by GCN4 and the Ssy1-Ptr3-Ssy5 amino acid sensor system. J Biol Chem. 2003;278:45882–45887. PubMed

Eng CH, Yu K, Lucas J, White E, Abraham RT. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci Signal. 2010;3(119) PubMed

Liao X, Butow RA. RTG1 and RTG2: two yeast genes required for a novel path of communication from mitochondria to the nucleus. Cell. 1993;72:61–71. PubMed

Cap M, Vachova L, Palkova Z. Yeast colony survival depends on metabolic adaptation and cell differentiation rather than on stress defense. J Biol Chem. 2009;284:32572–32581. PubMed PMC

Khamoui AV, Kim JS. Candidate mechanisms underlying effects of contractile activity on muscle morphology and energetics in cancer cachexia. Eur J Cancer Care. 2012;21:143–157. PubMed

Kirchman PA, Kim S, Lai CY, Jazwinski SM. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics. 1999;152:179–190. PubMed PMC

Boland ML, Chourasia AH, Macleod KF. Mitochondrial dysfunction in cancer. Front Oncol. 2013;3:292. PubMed PMC

Gueldener U, Heinisch J, Koehler GJ, Voss D, Hegemann JH. A second set of loxP marker cassettes for Cre-mediated multiple gene knockouts in budding yeast. Nucl Acids Res. 2002;30:e23. PubMed PMC

Sheff MA, Thorn KS. Optimized cassettes for fluorescent protein tagging in Saccharomyces cerevisiae. Yeast. 2004;21:661–670. PubMed

Gietz RD, Woods RA. Transformation of yeast by lithium acetate/single-stranded carrier DNA/polyethylene glycol method. Methods Enzymol. 2002;350:87–96. PubMed

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