COCEBI-1318; NO. OF PAGES 2
Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Cell regulation: Cell biology, fueling a renaissance in metabolism Jodi Nunnari and Johan Auwerx Current Opinion in Cell Biology 2015, 33:xx–yy
http://dx.doi.org/10.1016/j.ceb.2015.02.005 0955-0674/# 2015 Elsevier Ltd. All rights reserved.
Jodi Nunnari Department of Molecular and Cellular Biology, University of California, Davis 95616, USA e-mail: [email protected] Prof. Jodi Nunnari received her Ph.D. from Vanderbilt University in Pharmacology. She is currently a professor and chair of the Department of Molecular and Cellular Biology at the University of California, Davis, where her research is focused on understanding the mechanisms and functions of mitochondrial behavior in cells.
Johan Auwerx Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fe´de´rale de Lausanne, CH-1015 Lausanne, Switzerland e-mail: [email protected] Prof. Johan Auwerx received an M.D. and Ph.D. degree from the Katholieke Universiteit in Leuven, Belgium. He is currently professor at the Ecole Polytechnique Fe´de´rale in Lausanne, Switzerland, where he heads a research group that uses systems physiology and genetics to understand the link between transcription, mitochondria, metabolism, and aging.
Alterations in cellular metabolism predispose humans to systemic metabolic abnormalities and if left untreated to the development of severe and pervasive metabolic diseases, such as obesity, type 2 diabetes, hyperlipidemia, and atherosclerosis. Accordingly, a majority of metabolic research has been focused at understanding the ‘clinical’ manifestations of metabolic diseases. Recently, however there has been a renewed interest at a cellular level in understanding how metabolic pathways are intertwined with the key signaling pathways and cellular organelles, such as mitochondria, peroxisomes, or the endoplasmic reticulum, especially as organelle dysfunction is commonly an early ‘pre-clinical’ hallmark of metabolic derangement. Indeed, determinants of organellar form and functions, determined by the combined actions of large networks of genes, hormonal systems, and environmental and developmental factors, are highly regulated by metabolism. Therefore, it is timely to review how metabolic homeostasis is integrated with organelles and cellular and subcellular signaling pathways.
Signaling pathways Although many signaling pathways have a profound impact on metabolism, this issue is focused only on some of the most ancient cell autonomous signaling nodes on the premise that evolutionary conservation reflects their fundamental importance. Hardie reviews the recent insights gained by the determination of the crystal structure of the AMP-activated protein kinase (AMPK) heterotrimer — a primordial energy sensor — illuminates its complex mechanisms of activation. Another important aspect covered is the cellular organization of AMPK, which is activated on the lysosomal surface in close proximity and in coordination with mTORC1. Albert and Hall focus on recent insights into how the mTOR regulatory signaling pathways regulate cellular functions on both the intrinsic cellular and organismal levels, which highlights the fundamental importance of TOR in metabolic regulation. Lopez-Mejia and Fajas review how cell fates, such as proliferation, survival, growth, and senescence, are adapted to metabolism. In fact some prototypical cell cycle regulators, such as the cyclins, CDKs and E2Fs, are now emerging as essential regulators of mitochondrial function, allowing them to synchronize proliferative and metabolic responses.
Transcriptional pathways Several reviews in this issue cover transcriptional pathways that respond to and govern metabolism. Fan and Evans describe how the PPAR and ERR nuclear receptors are essential to control mitochondrial oxidative metabolism and to execute the inducible effects of the transcriptional coregulators, PGC1a and NCoR1. Stein and Schoonjans summarize how the function of another nuclear receptor, LRH-1, is fine tuned by post-translational www.sciencedirect.com
Current Opinion in Cell Biology 2015, 33:1–2
Please cite this article in press as: Nunnari J, Auwerx J: Editorial overview: Cell regulation: Cell biology, fueling a renaissance in metabolism, Curr Opin Cell Biol (2015), http://dx.doi.org/10.1016/ j.ceb.2015.02.005
COCEBI-1318; NO. OF PAGES 2
2 Cell regulation
modifications, in particular by SUMOylation. Changes in LRH-1 activity induced by SUMOylation allow hepatic LRH-1 to both control liver metabolism and impact ¨ st and metabolism beyond the liver. The review by O Pospisilik highlights the emerging picture of how key metabolites have crucial roles in chromatin control and illustrates that such regulatory modes can have transgenerational and developmental reprogramming effects, contributing to the metabolic inflexibility in metabolic diseases.
Cellular organelles and metabolism Historically many of the developments in metabolism have been spurred by studies of signaling and transcriptional pathways. However, recently major insights have been generated from the cell biology field through a better understanding of how the functions of cellular organelles intersect with metabolic pathways. Denzel and Antebi illustrate how the aminosugars UDP-GlcNAc and UDPGalNAc, produced by the hexosamine pathway link the metabolic status, protein quality control in the ER, and systemic fitness, which ultimately affects the aging process. Volmer and Ron discuss how alterations in lipid metabolism impact ER homeostasis through an interdependent relationship with the unfolded protein response. Organelle-linked lipid homeostasis through inter-organellear contact sites is also emerging as an important mode of regulation in cells. Lahiri et al. discuss common features used by membrane contact site components to mediate lipid exchange between organelles and the roles of contact sites beyond lipid exchange in the integration and regulation of cellular and organelle functions. Mitochondria represent the principle seat of cellular energy harvesting and are special amongst the intracellular organelles as their proteome is controlled by both the nuclear and mitochondrial genomes. With the exception of 13 electron transport chain components that are encoded by the mitochondrial DNA, the remainder of the 1200 mitochondrial proteins are encoded in the nuclear genome. These proteins are after their synthesis in the cytoplasm imported into the mitochondria through a complex import system. Opalin´ska and Meisinger review the compelling evidence that indicates that the activity of the machines responsible for the import of nuclear encoded mitochondrial proteins is regulated both directly by metabolites and by key metabolic signaling pathways. Despite this intricate and well-regulated protein import system, mitochondria remain prone to proteotoxic stress when protein production by the nuclear and mitochondrial genomes are not perfectly coordinated. As reviewed by Jovaisaite and Auwerx, mitochondria have evolved a specific defense system against proteotoxic stress, the mitochondrial unfolded protein response,
Current Opinion in Cell Biology 2015, 33:1–2
which synchronizes the mitochondrial and nuclear genomes to ensure the quality of the mitochondrial proteome. Mitochondrial fitness in cells is also maintained by mitochondrial turnover by autophagy or mitophagy. Eiyama and Okamoto review recent advances in a mammalian pathway comprised of a Ser/Thr kinase PINK1 and the E3 ubiquitin ligase Parkin, which act together to sense the functional metabolic status of mitochondria and upon activation ultimately mark and remove damaged mitochondria from cells via autophagy. Mitochondrial dynamics is intimately intertwined with mitochondrial quality control. As reviewed by Roy et al., recent findings now reveal that the components that mediate dynamics are under metabolic control. Thus, perhaps it is not surprisingly that defects in mitochondrial dynamics have been, in turn, linked to many metabolic disorders. As the seat of oxidative metabolism, mitochondria are also prone to oxidative stress caused by reactive oxygen species (ROS), which are potentially toxic byproducts of oxidative phosphorylation. However, ROS are also versatile signaling molecules with pleiotropic functions as reviewed by Reczek and Chandel, who also describe mechanisms for H2O2-dependent signal transduction. Given that mitochondria and ER are taking center stage in metabolic homeostasis, it became evident that optimizing communication between these organelles in different cells and tissues would be beneficial, the topic reviewed by Schinzel and Dillin. Organellar cell nonautonomous communication, by ERkines and mitokines, enables animals to mount coordinated and adaptive responses between organelles across different tissues.
Metabolites A review issue on metabolism would be nothing without a discussion of the regulatory roles and modes of storage and transport of metabolites Shi and Tu review the roles of the key hub metabolite, Acetyl-CoA, in metabolic homeostasis. Hashemi and Goodman discuss the many recent advances on the biogenesis regulation and turnover of lipid droplets, which is the major site for lipid storage in cells. Vanderperre et al. review our current knowledge of the structure and function of the mitochondrial pyruvate carrier (MPC) and discuss how dysfunction of the MPC could participate in various pathologies, including type 2 diabetes and cancer. The reviews in this issue illustrate how new insights obtained from molecular and cell biological studies advance not only our basic understanding of metabolic homeostasis but also how they reveal novel avenues for the diagnosis and management of common metabolic diseases. We hope that by the breadth and combination of areas covered in this issue, we will provide such an impetus.
www.sciencedirect.com
Please cite this article in press as: Nunnari J, Auwerx J: Editorial overview: Cell regulation: Cell biology, fueling a renaissance in metabolism, Curr Opin Cell Biol (2015), http://dx.doi.org/10.1016/ j.ceb.2015.02.005
Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Cell regulation: Cell biology, fueling a renaissance in metabolism Jodi Nunnari and Johan Auwerx Current Opinion in Cell Biology 2015, 33:xx–yy
http://dx.doi.org/10.1016/j.ceb.2015.02.005 0955-0674/# 2015 Elsevier Ltd. All rights reserved.
Jodi Nunnari Department of Molecular and Cellular Biology, University of California, Davis 95616, USA e-mail: [email protected] Prof. Jodi Nunnari received her Ph.D. from Vanderbilt University in Pharmacology. She is currently a professor and chair of the Department of Molecular and Cellular Biology at the University of California, Davis, where her research is focused on understanding the mechanisms and functions of mitochondrial behavior in cells.
Johan Auwerx Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fe´de´rale de Lausanne, CH-1015 Lausanne, Switzerland e-mail: [email protected] Prof. Johan Auwerx received an M.D. and Ph.D. degree from the Katholieke Universiteit in Leuven, Belgium. He is currently professor at the Ecole Polytechnique Fe´de´rale in Lausanne, Switzerland, where he heads a research group that uses systems physiology and genetics to understand the link between transcription, mitochondria, metabolism, and aging.
Alterations in cellular metabolism predispose humans to systemic metabolic abnormalities and if left untreated to the development of severe and pervasive metabolic diseases, such as obesity, type 2 diabetes, hyperlipidemia, and atherosclerosis. Accordingly, a majority of metabolic research has been focused at understanding the ‘clinical’ manifestations of metabolic diseases. Recently, however there has been a renewed interest at a cellular level in understanding how metabolic pathways are intertwined with the key signaling pathways and cellular organelles, such as mitochondria, peroxisomes, or the endoplasmic reticulum, especially as organelle dysfunction is commonly an early ‘pre-clinical’ hallmark of metabolic derangement. Indeed, determinants of organellar form and functions, determined by the combined actions of large networks of genes, hormonal systems, and environmental and developmental factors, are highly regulated by metabolism. Therefore, it is timely to review how metabolic homeostasis is integrated with organelles and cellular and subcellular signaling pathways.
Signaling pathways Although many signaling pathways have a profound impact on metabolism, this issue is focused only on some of the most ancient cell autonomous signaling nodes on the premise that evolutionary conservation reflects their fundamental importance. Hardie reviews the recent insights gained by the determination of the crystal structure of the AMP-activated protein kinase (AMPK) heterotrimer — a primordial energy sensor — illuminates its complex mechanisms of activation. Another important aspect covered is the cellular organization of AMPK, which is activated on the lysosomal surface in close proximity and in coordination with mTORC1. Albert and Hall focus on recent insights into how the mTOR regulatory signaling pathways regulate cellular functions on both the intrinsic cellular and organismal levels, which highlights the fundamental importance of TOR in metabolic regulation. Lopez-Mejia and Fajas review how cell fates, such as proliferation, survival, growth, and senescence, are adapted to metabolism. In fact some prototypical cell cycle regulators, such as the cyclins, CDKs and E2Fs, are now emerging as essential regulators of mitochondrial function, allowing them to synchronize proliferative and metabolic responses.
Transcriptional pathways Several reviews in this issue cover transcriptional pathways that respond to and govern metabolism. Fan and Evans describe how the PPAR and ERR nuclear receptors are essential to control mitochondrial oxidative metabolism and to execute the inducible effects of the transcriptional coregulators, PGC1a and NCoR1. Stein and Schoonjans summarize how the function of another nuclear receptor, LRH-1, is fine tuned by post-translational www.sciencedirect.com
Current Opinion in Cell Biology 2015, 33:1–2
Please cite this article in press as: Nunnari J, Auwerx J: Editorial overview: Cell regulation: Cell biology, fueling a renaissance in metabolism, Curr Opin Cell Biol (2015), http://dx.doi.org/10.1016/ j.ceb.2015.02.005
COCEBI-1318; NO. OF PAGES 2
2 Cell regulation
modifications, in particular by SUMOylation. Changes in LRH-1 activity induced by SUMOylation allow hepatic LRH-1 to both control liver metabolism and impact ¨ st and metabolism beyond the liver. The review by O Pospisilik highlights the emerging picture of how key metabolites have crucial roles in chromatin control and illustrates that such regulatory modes can have transgenerational and developmental reprogramming effects, contributing to the metabolic inflexibility in metabolic diseases.
Cellular organelles and metabolism Historically many of the developments in metabolism have been spurred by studies of signaling and transcriptional pathways. However, recently major insights have been generated from the cell biology field through a better understanding of how the functions of cellular organelles intersect with metabolic pathways. Denzel and Antebi illustrate how the aminosugars UDP-GlcNAc and UDPGalNAc, produced by the hexosamine pathway link the metabolic status, protein quality control in the ER, and systemic fitness, which ultimately affects the aging process. Volmer and Ron discuss how alterations in lipid metabolism impact ER homeostasis through an interdependent relationship with the unfolded protein response. Organelle-linked lipid homeostasis through inter-organellear contact sites is also emerging as an important mode of regulation in cells. Lahiri et al. discuss common features used by membrane contact site components to mediate lipid exchange between organelles and the roles of contact sites beyond lipid exchange in the integration and regulation of cellular and organelle functions. Mitochondria represent the principle seat of cellular energy harvesting and are special amongst the intracellular organelles as their proteome is controlled by both the nuclear and mitochondrial genomes. With the exception of 13 electron transport chain components that are encoded by the mitochondrial DNA, the remainder of the 1200 mitochondrial proteins are encoded in the nuclear genome. These proteins are after their synthesis in the cytoplasm imported into the mitochondria through a complex import system. Opalin´ska and Meisinger review the compelling evidence that indicates that the activity of the machines responsible for the import of nuclear encoded mitochondrial proteins is regulated both directly by metabolites and by key metabolic signaling pathways. Despite this intricate and well-regulated protein import system, mitochondria remain prone to proteotoxic stress when protein production by the nuclear and mitochondrial genomes are not perfectly coordinated. As reviewed by Jovaisaite and Auwerx, mitochondria have evolved a specific defense system against proteotoxic stress, the mitochondrial unfolded protein response,
Current Opinion in Cell Biology 2015, 33:1–2
which synchronizes the mitochondrial and nuclear genomes to ensure the quality of the mitochondrial proteome. Mitochondrial fitness in cells is also maintained by mitochondrial turnover by autophagy or mitophagy. Eiyama and Okamoto review recent advances in a mammalian pathway comprised of a Ser/Thr kinase PINK1 and the E3 ubiquitin ligase Parkin, which act together to sense the functional metabolic status of mitochondria and upon activation ultimately mark and remove damaged mitochondria from cells via autophagy. Mitochondrial dynamics is intimately intertwined with mitochondrial quality control. As reviewed by Roy et al., recent findings now reveal that the components that mediate dynamics are under metabolic control. Thus, perhaps it is not surprisingly that defects in mitochondrial dynamics have been, in turn, linked to many metabolic disorders. As the seat of oxidative metabolism, mitochondria are also prone to oxidative stress caused by reactive oxygen species (ROS), which are potentially toxic byproducts of oxidative phosphorylation. However, ROS are also versatile signaling molecules with pleiotropic functions as reviewed by Reczek and Chandel, who also describe mechanisms for H2O2-dependent signal transduction. Given that mitochondria and ER are taking center stage in metabolic homeostasis, it became evident that optimizing communication between these organelles in different cells and tissues would be beneficial, the topic reviewed by Schinzel and Dillin. Organellar cell nonautonomous communication, by ERkines and mitokines, enables animals to mount coordinated and adaptive responses between organelles across different tissues.
Metabolites A review issue on metabolism would be nothing without a discussion of the regulatory roles and modes of storage and transport of metabolites Shi and Tu review the roles of the key hub metabolite, Acetyl-CoA, in metabolic homeostasis. Hashemi and Goodman discuss the many recent advances on the biogenesis regulation and turnover of lipid droplets, which is the major site for lipid storage in cells. Vanderperre et al. review our current knowledge of the structure and function of the mitochondrial pyruvate carrier (MPC) and discuss how dysfunction of the MPC could participate in various pathologies, including type 2 diabetes and cancer. The reviews in this issue illustrate how new insights obtained from molecular and cell biological studies advance not only our basic understanding of metabolic homeostasis but also how they reveal novel avenues for the diagnosis and management of common metabolic diseases. We hope that by the breadth and combination of areas covered in this issue, we will provide such an impetus.
www.sciencedirect.com
Please cite this article in press as: Nunnari J, Auwerx J: Editorial overview: Cell regulation: Cell biology, fueling a renaissance in metabolism, Curr Opin Cell Biol (2015), http://dx.doi.org/10.1016/ j.ceb.2015.02.005
