Nucleus to Mitochondria: Lost in Transcription, Found in Translation

Developmental Cell

Previews DM-defined ventral midline. Potentially inconsistent with this model, unilateral overexpression of BMP4 did not shift the position of the DM. The authors speculate that levels of BMP signaling may be close to maximal in the forming DM, and thus changes in the behavior of CE-derived SPM would result only from a decrease in BMP signaling. Another scenario to consider is that the ligand activating BMP regulation of the SPM may be a heterodimer of BMP4 and a second ligand expressed in limiting quantities. Thus, much remains to be discovered about the mechanism ensuring symmetrical BMP signaling. Embryos surviving 72 hr after Noggin electroporation displayed aberrant connections between the DM and lung mesenchyme, resulting in mis-positioning of this visceral tissue. Such observations emphasize that irregularities occurring during VFM (fifth week of human gestation) can result in severe structural defects later in development and at birth. As Arraf

et al. (2016) comment, this work, as well as that of others (Madabhushi and Lacy, 2011; Gavrilov and Lacy, 2013), points to a central role for BMP signaling in coordinating multiple events during VFM. Thus, future studies probing interactions between BMP and other key signaling pathways (SHH, WNT, FGF) promise a deeper understanding of tissue morphogenesis and organ positioning and of how perturbations during early embryogenesis will impact viability during fetal development and at birth. ACKNOWLEDGMENTS We thank Aleksandra Samardzic for her work on the illustrations. Our research is funded by grants from the NIH (R01-HD072499 and NIH/NCI CCSG P30 CA008748).

REFERENCES Arraf, A.A., Yelin, R., Reshef, I., Kispert, A., and Schultheiss, T.M. (2016). Dev. Cell 37, this issue, 571–580.

Davis, N.M., Kurpios, N.A., Sun, X., Gros, J., Martin, J.F., and Tabin, C.J. (2008). Dev. Cell 15, 134–145. Gavrilov, S., and Lacy, E. (2013). Curr. Opin. Genet. Dev. 23, 461–469. Gros, J., and Tabin, C.J. (2014). Science 343, 1253–1256. Madabhushi, M., and Lacy, E. (2011). Dev. Cell 21, 907–919. Mahadevan, A., Welsh, I.C., Sivakumar, A., Gludish, D.W., Shilvock, A.R., Noden, D.M., Huss, D., Lansford, R., and Kurpios, N.A. (2014). Dev. Cell 31, 690–706. Mutsaers, S.E., Birnie, K., Lansley, S., Herrick, S.E., Lim, C.B., and Preˆle, C.M. (2015). Front. Pharmacol. 6, http://dx.doi.org/10.3389/fphar.2015. 00113. Welsh, I.C., Thomsen, M., Gludish, D.W., AlfonsoParra, C., Bai, Y., Martin, J.F., and Kurpios, N.A. (2013). Dev. Cell 26, 629–644. Winters, N., and Bader, D. (2013). J. Dev. Biol. 1, 64–81. Winters, N.I., Thomason, R.T., and Bader, D.M. (2012). Development 139, 2926–2934.

Nucleus to Mitochondria: Lost in Transcription, Found in Translation Julie St-Pierre1,2,* and Ivan Topisirovic2,3,4,5,* 1Goodman

Cancer Research Centre, McGill University, Montre´al, QC H3A 1A3, Canada of Biochemistry 3Department of Oncology 4Department of Experimental Medicine McGill University, Montreal, QC H3A 1A3, Canada 5Lady Davis Institute, SMBD JGH, McGill University, Montre ´ al, QC H3T 1E2, Canada *Correspondence: [email protected] (J.S.-P.), [email protected] (I.T.) http://dx.doi.org/10.1016/j.devcel.2016.06.003 2Department

Mitochondrial genes reside in the nucleus and mitochondria. In a recent paper in Nature, Couvillion et al. (2016) describe their development of a ‘‘mitoribosome profiling’’ approach and demonstrate that changes in expression of nuclear- and mitochondrial-encoded genes are coordinated at the level of translation during metabolic adaptation to fuel source changes.

Mitochondrial metabolism is highly adaptable and can respond efficiently to physiological and environmental cues. These integrated responses require communication between the nuclear and mitochondrial compartments, given that the mitochondrial proteome is the product of 490 Developmental Cell 37, June 20, 2016

both nuclear and mitochondrial genomes. Indeed, the majority of proteins in mitochondria are nuclear-encoded (Friedman and Nunnari, 2014). However, several proteins (e.g., subunits of the electron transport chain, along with maturases), as well as mitochondrial transfer and

ribosomal RNAs, are encoded by the mitochondrial genome (Friedman and Nunnari, 2014). The understanding of the mechanisms that coordinate expression of proteins encoded by nuclear and mitochondrial DNA during metabolic stress remains incomplete. To address

Developmental Cell

Previews this challenge, Couvillion and Cbp6 for COB mRNA) and/or colleagues (2016) interrorepressors (e.g., Smt1p for gated changes in nuclearATP8/ATP6 mRNA) of mitoand mitochondrial-encoded chondrial translation. Collecgene expression in response tively, these findings suggest to switching metabolism from that the rapid response to fermentation to respiration in the shift from fermentation budding yeast. They discovto respiratory metabolism in ered that the expression of budding yeast encompasses key mitochondrial- and nuhighly orchestrated changes clear-encoded genes is inin cytoplasmic and mitotegrated at the level of chondrial translation through translation. unidirectional cytosol-mitoIn order to rapidly stimulate chondrial communication mitochondrial metabolism, the (Figure 1). authors switched the carThis work has important imbon source from glucose to plications and raises several glycerol, which forces yeast challenging questions. One to rely on mitochondria for central question is to deterATP production and stimulates mine whether similar mechamitochondrial biogenesis (Jolnisms exist in other eukaryFigure 1. Unidirectional Communication between Cytoplasmic and low et al., 1968). This switch otes. Moreover, relatively Mitochondrial Translation Underpins Coordinated Expression of Nuclear- and Mitochondrial-Encoded Components of the Electron from fermentation to respiralittle is known regarding the Transport Chain tion augmented nuclear- and spatiotemporal regulation of Upon rapid induction of mitochondrial metabolism in budding yeast caused by mitochondrial-encoded elecnuclear- and mitochondrialswitching from fermentation to respiration, translation of nuclear-encoded (red) and mitochondrial-encoded (green) electron transport chain mRNAs, and tron transport chain mRNA encoded gene expression in particular those encoding components of the complexes III (blue), IV levels, whereas expression of upon acute versus chronic (orange), and V (yellow), by cytoplasmic (red) or mitochondrial (green) riboboth nuclear- and mitochonexposure to environmental somes is highly coordinated. Changes in cytoplasmic translation appear to drial-encoded RNAs corresignals. The findings of Couunilaterally modulate mitochondrial translation (red arrow). sponding to the mitoribosomal villion and colleagues (2016) proteins appeared to be less imply that rapid engagement affected. Distinctly, the changes in the in translation of mRNA-encoding compo- of mitochondrial metabolism is achieved levels of nuclear- and mitochondrial-en- nents of complex III (ubiquinol-cyto- through coordination of cytoplasmic coded electron transport chain mRNAs chrome c oxidoreductase) and IV (cyto- and mitochondrial translational programs. exhibited remarkably different dynamics, chrome c oxidase) (Figure 1). These However, it remains unclear whether the whereby the increase in mitochondrial results demonstrate that, in contrast to observed translational mechanism is transcripts appeared to be significantly temporal discordance in the alterations implicated in promoting mitochondrial delayed relative to their nuclear-encoded in nuclear- and mitochondrial-encoded biogenesis induced by transferring yeast counterparts. mRNA expression, highly coordinated from glucose to glycerol (Jollow et al., Given this notable lack of synchrony in changes in cytoplasmic and mitochon- 1968). In budding yeast, the pivotal postthe changes in expression of mitochon- drial translation underpin metabolic adap- transcriptional regulator Puf3p associates drial- and nuclear-encoded mRNAs dur- tations in budding yeast. with the vast majority of the nuclear-ening rapid stimulation of mitochondrial Interestingly, selective blocking of cyto- coded mitochondrial mRNAs via specific metabolism, the authors then examined plasmic translation using cycloheximide 30 UTR elements, whereby it is thought to alterations in cytoplasmic and mitochon- caused rapid changes in the synthesis of play a major role in localization, translation, drial translation. They modified the ribo- mitochondrial-encoded proteins, even in and degradation of nuclear-encoded mitosome profiling approach to allow direct the absence of metabolic adaptations, chondrial mRNAs (Gerber et al., 2004). monitoring of mitochondrial translation. whereas major changes in cytoplasmic Puf3p levels are rapidly downregulated Mitoribosome profiling revealed that translation in response to nutrient switch- during conditions that increase mitochonacute mitochondrial reprogramming in ing were not elicited by blocking mito- drial biogenesis, including switching from response to the switch in nutrients is chondrial translation with pentamidine, glucose to glycerol (Garcı´a-Rodrı´guez accompanied by downregulation of com- mitochondrial import with the uncoupler et al., 2007), which suggests that the role plex V (ATP synthase) in favor of complex CCCP, or using a yeast strain lacking of Puf3p may be to coordinate expression IV (cytochrome c oxidase) mRNA transla- mitochondrial DNA. This apparent depen- of nuclear-encoded genes that govern tion. Parallel translational perturbations dence of changes in mitochondrial trans- mitochondrial biogenesis by orchestrating were observed in the pools of nuclear-en- lation in response to alteration in the cyto- multiple post-transcriptional mechanisms. coded mRNAs, whereby the translation of plasmic translatome may be explained by These Puf3p-dependent mechanisms are complex V (ATP synthase) mRNAs was upregulation of cytoplasmic translation of likely to cooperate with the observed decreased with a concomitant increase specific mRNAs encoding activators (e.g., synchronous perturbations in cytoplasmic Developmental Cell 37, June 20, 2016 491

Developmental Cell

Previews and mitochondrial translatomes to simultaneously modulate mitochondrial number and function in response to metabolic stress. Although the link between cytoplasmic and mitochondrial translation in evolutionarily higher eukaryotes remains to be established, it has been reported in both flies and humans that adaptations to changes in nutrient levels appear to be mediated at least in part by translational perturbations in nuclear-encoded mitochondrial mRNAs. These changes appear to be mediated via the Target of Rapamycin (TOR)/eukaryotic translation initiation 4E (eIF4E)-binding protein pathway (Morita et al., 2013; Zid et al., 2009). Additionally, transcriptional mechanisms appear to play a more prominent role in higher eukaryotes than in budding yeast, in particular in the later phases of the metabolic adaptation response. For instance, in mammals, the PGC-1a-NRF1-TFAM transcriptional axis is a key regulator of mitochondrial metabolism when adapting to intracellular and extracellular signals. In response to environmental signals, PGC1a simultaneously modulates the expression of NRF1 and TFAM, which are

492 Developmental Cell 37, June 20, 2016

central transcriptional regulators of nuclear- and mitochondrial-encoded mitochondrial protein levels, respectively (Wu et al., 1999). This demonstrates the existence of coordinated transcriptional responses between mitochondria and nucleus when adapting to environmental changes. Interestingly, there is a yeast counterpart to TFAM called ABF2. In contrast to TFAM, however, ABF2 does not appear to play a direct role in the transcriptional initiation of mitochondrial-DNA (Xu and Clayton, 1992), highlighting some potential differences between yeast and mammalian systems. Finally, it will be crucial to examine the implication of these discoveries in the diseases characterized by mutations in mitochondrial translation regulators, including the late-onset Leigh syndrome (Weraarpachai et al., 2009), as well as pathological conditions in which metabolic adaptations caused by fluctuations in nutrient supply are prominent, like diabetes and cancer.

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REFERENCES Couvillion, M.T., Soto, I.C., Shipkovenska, G., and Churchman, L.S. (2016). Nature 533, 499–503.

Zid, B.M., Rogers, A.N., Katewa, S.D., Vargas, M.A., Kolipinski, M.C., Lu, T.A., Benzer, S., and Kapahi, P. (2009). Cell 139, 149–160.