BIOENERGETICS Mitochondrial ETC Activity Complexes I, II, III, & IV Mitochondrial Activity Complex V Oxygen Consumption/Glycolysis Mitochondrial Membrane Potential Citrate Synthase Activity BIOCHEMICALS · ASSAY KITS · ANTIBODIES PROTEINS · RESEARCH SERVICES Visit www.CaymanChem.com/Bioenergetics for more information on Cayman’s Mitochondrial Assays Call us at 800·364·9897 or Email us at [email protected] Foreword We are pleased to introduce the latest edition of Cell Press Selections. These editorially curated reprint collections highlight a particular area of life science by bringing together articles from the Cell Press journal portfolio. In this selection, we present recent insights into the diverse roles of mitochondria. Mitochondria perform diverse yet interconnected cellular functions and are dynamically regulated by complex signaling pathways. Interest in this fascinating organelle has recently undergone a renaissance, due to a series of discoveries revealing that mitochondrial function goes beyond the generation of molecular fuel. Mitochondria also play a central role in thermogenesis, differentiation, and cell death and influence an organism’s physiology, as well as its pathology. The driving forces behind these discoveries have been in the development of animal models, systems-based approaches, and dynamic imaging techniques and are critical in unraveling the significance and complexity of mitochondrial behavior. A comprehensive inventory on mitochondrial proteins over the past decade indicates that mammalian mitochondria contain over 1,500 proteins, which vary in a tissue-dependent manner. Not surprisingly, mitochondria are tasked with a myriad of critical roles in anything from regulating inflammatory responses to determining cellular response to chemotherapy. The articles in this selection explore the breadth of this organelle’s function (and dysfunction). We hope that you will enjoy reading this collection of articles and will visit www.cell.com to find other high-quality research and review articles across this rapidly growing field. Finally, we are grateful for the generosity of Cayman Chemical, who helped to make this reprint collection possible. For more information about Cell Press Selections: Gordon Sheffield Program Director, Cell Press Selections g.sheffi[email protected] 617-386-2189 MITOCHONDRIALETC Individually Screen Complexes I, II, II/III, & IV Identify the Inhibition RI6SHFLĆF&RPSOH[HV No Antibodies Required Adaptable to HTS BIOCHEMICALS · ASSAY KITS · ANTIBODIES PROTEINS · RESEARCH SERVICES Visit www.CaymanChem.com/Bioenergetics for more information on Cayman’s Mitochondrial Assays Call us at 800·364·9897 or Email us at [email protected] Multifaceted Mitochondria Reviews Mitochondria: In Sickness and in Health Jodi Nunnari and Anu Suomalainen Stress-Responsive Regulation of Mitochondria T. Kelly Rainbolt, Jaclyn M. Saunders, and R. Luke Wiseman through the ER Unfolded Protein Response Mitochondria: From Cell Death Executioners to Atsuko Kasahara and Luca Scorrano Regulators of Cell Differentiation Self and Nonself: How Autophagy Targets Mitochondria Felix Randow and Richard J. Youle and Bacteria Articles Mitochondrial Cristae Shape Determines Respiratory Sara Cogliati, Christian Frezza, Maria Eugenia Soriano, Chain Supercomplexes Assembly and Respiratory Tatiana Varanita, Ruben Quintana-Cabrera, Mauro Corrado, Efficiency Sara Cipolat, Veronica Costa, Alberto Casarin, Ligia C. Gomes, Ester Perales-Clemente, Leonardo Salviati, Patricio Fernandez-Silva, Jose A. Enriquez, and Luca Scorrano The Mitochondrial Chaperone TRAP1 Promotes Marco Sciacovelli, Giulia Guzzo, Virginia Morello, Christian Neoplastic Growth by Inhibiting Succinate Frezza, Liang Zheng, Nazarena Nannini, Fiorella Calabrese, Dehydrogenase Gabriella Laudiero, Franca Esposito, Matteo Landriscina, Paola Defilippi, Paolo Bernardi, and Andrea Rasola The Intrinsic Apoptosis Pathway Mediates the Pro- Callista Yee, Wen Yang, and Siegfried Hekimi Longevity Response to Mitochondrial ROS in C. elegans ROS-Triggered Phosphorylation of Complex II by Fgr Rebeca Acín-Pérez, Isabel Carrascoso, Francesc Baixauli, Kinase Regulates Cellular Adaptation to Fuel Use Marta Roche-Molina, Ana Latorre-Pellicer, Patricio Fernández- Silva, María Mittelbrunn, Francisco Sanchez-Madrid, Acisclo Pérez-Martos, Clifford A. Lowell, Giovanni Manfredi, and José Antonio Enríquez 8=7< B63 230/B3 EWbV1SZZ>`Saa@SdWSea 7\aWUVbO\R^S`a^SQbWdSWaO^]eS`TcZ B]^`]^SZg]c``SaSO`QVT]`eO`RTOabS`bc`\b] Q][PW\ObW]\BVOb¸aeVgeS]TTS``SORS`a 1SZZ>`Saa@SdWSea=c`W\aWUVbTcZOcbV]`WbObWdS OQ`WbWQOZSfO[W\ObW]\]TbVSSdWRS\QSbVOb `SdWSea´^cPZWaVSROQ`]aabVSZWTSaQWS\QSaW\ ^`]d]YSabV]cUVbO\RTOQWZWbObSaRWaQcaaW]\ ]c`^`W[O`g`SaSO`QVO\RB`S\RaX]c`\OZa´U] eWbVW\aQWS\bW¿QQ][[c\WbWSa PSg]\Rag\bVSaWaO\R]TTS`O^]W\b]TdWSe 4W\Rg]c`eOg eWbV1SZZ>`Saa@SdWSea eeeQSZZQ][`SdWSea Leading Edge Review Mitochondria: In Sickness and in Health Jodi Nunnari1,* and Anu Suomalainen2,3,* 1Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA 2Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland 3Department of Neurology, Helsinki University Central Hospital, 00290 Helsinki, Finland *Correspondence: [email protected] (J.N.), anu.wartiovaara@helsinki.fi (A.S.) DOI 10.1016/j.cell.2012.02.035 Mitochondria perform diverse yet interconnected functions, producing ATP and many biosynthetic intermediates while also contributing to cellular stress responses such as autophagy and apoptosis. Mitochondria form a dynamic, interconnected network that is intimately integrated with other cellular compartments. In addition, mitochondrial functions extend beyond the bound- aries of the cell and influence an organism’s physiology by regulating communication between cells and tissues. It is therefore not surprising that mitochondrial dysfunction has emerged as a key factor in a myriad of diseases, including neurodegenerative and metabolic disorders. We provide a current view of how mitochondrial functions impinge on health and disease. Introduction ancestry of mitochondria and bacteriophage-related mtDNA Mitochondria arose from an alpha-proteobacterium engulfed by maintenance systems make the organelle susceptible to antimi- a eukaryotic progenitor (Lane and Martin, 2010). Like their bacte- crobial drugs: for example, mitochondrial translation is targeted rial ancestor, mitochondria are comprised of two separate and by common antibiotics that block microbial ribosomes (amino- functionally distinct outer (OMs) and inner membranes (IMs) glycosides, tetracyclines) (Hutchin et al., 1993; van den Bogert that encapsulate the intermembrane space (IMS) and matrix and Kroon, 1981), and mtDNA maintenance is affected by anti- compartments. They also contain a circular genome, mitochon- viral nucleoside analogs (Arnaudo et al., 1991). The genetic risk drial DNA (mtDNA), that has been reduced during evolution factors underlying drug sensitivity of mitochondrial function are through gene transfer to the nucleus. mtDNA is organized into expected to be numerous, but challenging to identify. discrete nucleoids in the matrix. Interestingly, the closest The considerable resources a cell must provide to maintain the relatives of many mtDNA-modifying enzymes, such as mtDNA mitochondrial compartment underscores the varied essential polymerase, are bacteriophage proteins (Lecrenier et al., 1997; roles it plays. This is further demonstrated by the fact that mito- Tiranti et al., 1997), suggesting that an infection of the mitochon- chondrial dysfunction is associated with an increasingly large drial ancestor contributed to the development of mtDNA mainte- proportion of human inherited disorders and is implicated nance machinery. In animals, mtDNA inheritance is almost in common diseases, such as neurodegenerative disorders, exclusively maternal, and paternal mtDNA is actively destroyed cardiomyopathies, metabolic syndrome, cancer, and obesity. in many species immediately after fertilization (Al Rawi et al., Below we review new developments in mitochondrial biology 2011; Sato and Sato, 2011). and discuss their relevance for human disease. Advances in proteomic, genomic, and bioinformatic ap- proaches have provided a comprehensive inventory of mito- Mitochondrial Defects Cause Diverse and Complex chondrial proteins in various eukaryotes (Gaston et al., 2009; Human Diseases Mootha et al., 2003; Pagliarini et al., 2008; Sickmann et al., Human mitochondrial disorders are a genetically heterogeneous 2003). This inventory indicates that mammalian mitochondria group of different diseases, caused by mutations in mitochon- contain over 1,500 proteins, which vary in a tissue-dependent drial and/or nuclear DNA, which encompass almost all fields of manner. Because mtDNA encodes only 13 of these proteins, medicine (Ylikallio and Suomalainen, 2012). Mitochondrial mitochondria depend on the nucleus and other cellular compart- diseases can affect any organ system, manifest at any age, ments for most of their proteins and lipids. Nuclear-encoded and, depending on where the gene defect lies, be inherited mitochondrial proteins are actively imported and sorted into from an autosome, the X chromosome, or maternally. Currently, each mitochondrial compartment (Neupert and Herrmann, mitochondrial disorders cannot be cured, and available treat- 2007; Schmidt et al., 2010), followed by coordinated assembly ments are directed at relieving symptoms (Suomalainen, 2011). into macromolecular complexes,