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The Yeast Retrograde Response as a Model of Intracellular Signaling of Mitochondrial Dysfunction

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The Yeast Retrograde Response as a Model of Intracellular Signaling of Mitochondrial Dysfunction

S Michal Jazwinski et al. Front Physiol.

Abstract

Mitochondrial dysfunction activates intracellular signaling pathways that impact yeast longevity, and the best known of these pathways is the retrograde response. More recently, similar responses have been discerned in other systems, from invertebrates to human cells. However, the identity of the signal transducers is either unknown or apparently diverse, contrasting with the well-established signaling module of the yeast retrograde response. On the other hand, it has become equally clear that several other pathways and processes interact with the retrograde response, embedding it in a network responsive to a variety of cellular states. An examination of this network supports the notion that the master regulator NFκB aggregated a variety of mitochondria-related cellular responses at some point in evolution and has become the retrograde transcription factor. This has significant consequences for how we view some of the deficits associated with aging, such as inflammation. The support for NFκB as the retrograde response transcription factor is not only based on functional analyses. It is bolstered by the fact that NFκB can regulate Myc-Max, which is activated in human cells with dysfunctional mitochondria and impacts cellular metabolism. Myc-Max is homologous to the yeast retrograde response transcription factor Rtg1-Rtg3. Further research will be needed to disentangle the pro-aging from the anti-aging effects of NFκB. Interestingly, this is also a challenge for the complete understanding of the yeast retrograde response.

Keywords: NFκB; RTG genes; Saccharomyces cerevisiae; metabolism; mitophagy; replicative lifespan; retrograde response; stress.

Figures

Figure 1
Figure 1
Dysfunctional mitochondria trigger a retrograde response in yeast and in round worms. In yeast, a drop in mitochondrial membrane potential (ΔΨm) initiates retrograde signaling through Rtg2, by preventing the Mks1-Bmh1/2 complex from inhibiting the partial dephosphorylation of Rtg3 in the Rtg1–Rtg3 retrograde transcription factor which is stimulated by Rtg2. Rtg1–Rtg3 translocates from the cytoplasm to the nucleus where it activates the expression of retrograde response target genes. The nutrient-responsive, target of rapamycin (TOR) complex 1 (TORC1) blocks the retrograde response both upstream and downstream of Rtg2. TORC1 also suppresses the stimulatory effect of Ras2 on retrograde signaling. In the worm, a signal(s) elicited by dysfunctional mitochondria activate anyone of at least three retrograde signaling pathways defined by the transcription factor which is activated. The transcription factor can be HIF-1, activated by reactive oxygen species (ROS), UBL-5 and DEV-1, or the putative transcription factor CEH-23.
Figure 2
Figure 2
Retrograde signaling in yeast and human. In yeast, respiring mitochondria in non-dividing, stationary phase cells signal the retrograde response that activates both retrograde response target genes, similar to those in dividing cells, and mitophagy genes. This results in the metabolic adaptation to stationary phase. Aup1, a protein phosphatase in the intermembrane space in mitochondria, is essential for this gene induction. Rtg1–Rtg3 is the retrograde transcription factor. On the other hand, dysfunctional mitochondria in growing cells trigger the classical retrograde response with activation of retrograde response target genes. Rtg2 plays an essential role in this process. Gem1 is a Miro homolog in yeast which is important for maintaining junctions between mitochondria and the endoplasmic reticulum. By analogy with mammalian cells, it would also tether the mitochondria to the cytoskeleton. In human cells, a drop in mitochondrial membrane potential (ΔΨm) recruits Parkin by the PINK1 protein kinase to the mitochondrial membrane. Parkin mediates ubiquitylation of Miro, which releases the mitochondria from the cytoskeleton and also, presumably, from the endoplasmic reticulum. This facilitates the removal of dysfunctional mitochondria by mitophagy. Sequestosome 1 (p62) aggregates proteins polyubiquitinated by Parkin on the surface of mitochondria. p62 is known to stimulate NFκB, which among its many target genes has Myc. The Myc–Max dimer is homologous to Rtg1–Rtg3. Transcription of Myc is activated in human cells devoid of mtDNA, and Myc itself activates the transcription of metabolic genes, typical for the retrograde response. The production of reactive oxygen species (ROS) by the mitochondria may elicit responses as well.
Figure 3
Figure 3
Side-by-side comparison of the retrograde response controlled by the heterodimeric transcription factors Rtg1–Rtg3 in yeast and NFκB in mammalian cells. In contrast to the three Rtg proteins in yeast, NFκB activators, inhibitors and transcription factors have evolved into a wide spectrum of subunits to elicit specific response patterns to a variety of stressors. Common to both pathways is their activation by mitochondrial dysfunction involving reactive oxygen species (ROS) and changes in mitochondrial membrane potential (ΔΨm). Another common activator that responds to external stressors is RAS (Ras2 in yeast). Furthermore, both pathways are modulated by TOR through LST8. LST8 dissociates from mTOR under stress, although it is not known whether this is true of TOR in yeast. Regulation of autophagy by TOR impinges on both pathways, as well. The adaptive response of both pathways to mitochondrial dysfunction includes upregulation of glycolysis to compensate for energy deficiency.
Figure 4
Figure 4
Metabolic adaptations to loss of biosynthetic intermediate production by a truncated tricarboxylic acid (TCA) cycle. The loss of the electron transport chain interrupts the TCA cycle at the succinate dehydrogenase reaction. This prevents the utilization of the TCA cycle for production of biosynthetic intermediates. In yeast, the glyoxylate cycle is induced. This allows acetyl-coenzyme A (acetyl-CoA) to be used for the synthesis of the TCA cycle metabolites citrate and malate, in reactions that conserve the two carbons of acetate. This, in turn, allows the first three reactions of the TCA cycle to proceed with the synthesis of α-ketoglutarate, which can be converted to glutamate, the ultimate source of nitrogen in biosynthesis (not shown here). In human cells, a related metabolic adaptation occurs. This adaptation is the reductive carboxylation of α-ketoglutarate to yield isocitrate, which in turn is a source of TCA cycle intermediates citrate and malate at the same time generating acetyl-CoA for lipid biosynthesis. The ultimate source of α-ketoglutarate in these reactions is glutamine, which allows the use of glucose for production of energy in glycolysis as well as for biosynthetic reactions. In both yeast and human, TCA cycle metabolites are used as macromolecular precursors.

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