Mitochondria, Metabolism and Disease

Mitochondria, Metabolism and Disease

Thursday, April 10, 2014

The New York Academy of Sciences

Presented By

 

Mitochondria are the cell's "power plants" and serve a critical role in global metabolism. Accordingly, dysfunction or damage of mitochondria can greatly perturb metabolism, and underlies a diverse range of human diseases, ranging from neurodegenerative conditions (ALS, Alzheimer's and Parkinson's diseases), epilepsy, psychiatric illness and autism, to atherosclerotic heart disease, stroke, liver disease, type 2 diabetes and cancer. The broad impact of mitochondria in so many diseases makes them an important focus for study as well as a target for therapy. This symposium brings together cutting-edge investigators with the shared goal of characterizing and curing diseases that arise from aberrant mitochondrial metabolism.

*Reception to follow.

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Agenda

* Presentation titles and times are subject to change.


Thursday April 10, 2014

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Steven S. Gross, PhD, Weill Cornell Medical College

9:20 AM

Overview of Mitochondrial Disorders
Salvatore DiMauro, MD, Columbia University Medical Center

10:00 AM

Systems Biology of Muscle Mitochondrion
Robert Balaban, PhD, National Heart. Lung, and Blood Institute, NIH

10:40 AM

Coffee break

11:10 AM

The Metabolic Response to Mitochondrial Dysfunction in Human Cells
Robert Bao, PhD, Massachusetts General Hospital

11:50 AM

Functionalizing the Unannotated Mitochondrial Proteome
Jared Rutter, PhD, University of Utah School of Medicine

12:30 PM

Networking lunch

1:30 PM

Pancreatic Cancer Depends on a Non-Canonical Glutamine Metabolism Pathway
Costas A. Lyssiotis, PhD, Weill Cornell Medical College

2:10 PM

Profiling Identifies an Essential Role for Huntingtin Protein in Mitochondrial Respiration and Metabolism
Steven S. Gross, PhD, Weill Cornell Medical College

2:50 PM

Coffee break

3:20 PM

How Yeast Cells Decide to Make Mitochondria
Benjamin P. Tu, PhD, UT Southwestern Medical Center

4:00 PM

Clinical Development of the First Cardiolipin Therapeutic for Diseases Associated with Mitochondrial Dysfunction
Hazel H. Szeto, MD, PhD, Weill Cornell Medical College

4:40 PM

Closing remarks
Steven S. Gross, PhD, Weill Cornell Medical College

5:00 PM

Networking reception

6:00 PM

Close

Speakers

Organizers

Vamsi K. Mootha, MD

Harvard Medical School

Vamsi Mootha is an Investigator of the Howard Hughes Medical Institute, Professor of Systems Biology and Medicine at Harvard Medical School, and a Senior Associate Member of the Broad Institute. He runs a research laboratory dual localized between Massachusetts General Hospital and the Broad Institute. Mootha’s research is primarily focused on the mitochondrion, the "powerhouse of the cell," and its role in human disease. Mootha’s group has produced a near-comprehensive, mitochondrial protein inventory called MitoCarta. MitoCarta now serves as a blueprint for molecular and systematic studies of mitochondria and has been widely used by the research community. Mootha and colleagues have used this inventory to discover the mitochondrial calcium uniporter, a major channel of communication between mitochondria and rest of the cell, as well as more than one dozen disease genes that underlie severe, metabolic diseases. He utilizes a multidisciplinary approach that combines mathematics, computer science, biochemistry, and clinical genetics. Mootha received his undergraduate degree in mathematical and computational science at Stanford University, where he graduated Phi Beta Kappa with highest honors. He received his M.D. from Harvard Medical School in the Harvard-MIT Division of Health Sciences and Technology, where his thesis work was focused on mitochondrial bioenergetics. He subsequently completed his internship and residency in internal medicine at Brigham and Women's Hospital, after which he completed postdoctoral fellowship training at the Whitehead Institute/MIT Center for Genome Research. He has received numerous honors, including a MacArthur Foundation Fellowship, the Judson Daland Prize of the American Philosophical Society, election to the Association of American Physicians, the 2014 Keilin Medal of the Biochemical Society, and a 2014 Padma Shri from the Government of India.

Steven Gross, PhD

Weill Cornell Medical College

Steven S. Gross is Professor of Pharmacology, Director of the Mass Spectrometry Core Facility and Director of Advanced Training in Pharmacology at the Weill Cornell Medical College. He obtained his PhD in Biomedical Science from the Mount Sinai School of Medicine in 1982. With exception of 2-3 years spent at the William Harvey Research Institute in London, England - working with Nobel Laureate, Sir John Vane - his entire research career has been at Cornell Medical College. Dr. Gross’s major research interest has been cell–cell communication, with a focus on nitric oxide (NO) and reactive molecules as mediators of cell signaling. In the late 1980s, Dr. Gross and colleagues identified L-arginine as the precursor of NO in blood vessels and demonstrated that NO synthase inhibition elevates blood pressure in animals, uncovering a physiological role for NO in controlling blood pressure and vascular tone. Since then, research efforts have been directed toward elucidating the enzymes and mechanisms that regulate NO synthesis in cells. His basic studies have provided fundamental insights into the therapeutic control of NO synthesis, resulting in core technologies and patents for the creation of ArgiNOx Inc., a biotech start-up that seeks to develop novel NO-based drugs. Over the past several years, his lab established an MS-based platform for broad untargeted metabolite profiling of complex cell extracts and biofluids- this platform is now being applied to attack diverse problems in biomedicine that benefit from comprehensive system-wide knowledge of metabolic perturbations that arise from drugs, gene mutations and disease states. In 2011, Dr. Gross received from the American Chemical Society an award for Achievements in Mass Spectrometry. Dr. Gross is a founder and Board Director of the Nitric Oxide Society, Co-chairs the Steering Committee of the Biochemical Pharmacology Discussion Group (BPDG) at NYAS and has contributed to the organization of an ongoing series of NYAS symposia on biomedical research topics in the area of metabolism and metabolomics. The present meeting on Mitochondria, Metabolism and Disease is the most recent installment to this NYAS symposium series.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Robert Balaban, PhD

National Heart, Lung, and Blood Institute, NIH

Dr. Robert Stephen Balaban is currently the Scientific Director of the National Heart, Lung, and Blood Institute (NHLBI) and the Chief of the Laboratory of Cardiac Energetics, Division of Intramural Research, NHLBI. Dr. Balaban received his BS from the University of Miami in 1971 in Biology and Chemistry and his Ph.D. from Duke University in 1980 in Physiology and Pharmacology. Dr. Balaban was awarded a NATO Fellowship to the Department of Biochemistry at the University of Oxford in 1981. He joined the NHLBI in 1982 as a staff fellow in the Laboratory of Kidney and Electrolyte Metabolism. In 1988 he was named the Chief of the newly formed Laboratory of Cardiac Energetics. He was appointed to Scientific Director of the Laboratory Research Program in 1999. He became the overall Scientific Director of the NHLBI intramural research program in 2004. The research theme of Dr. Balaban’s laboratory is the systems biology of the mitochondria with a focus on the energy metabolism of the heart, liver and skeletal muscle along with the use of non-linear optical techniques for imaging cellular events related to mitochondrial function, in vivo. Dr. Balaban is the author of over 300 peer reviewed manuscripts and 8 US patent applications. Dr. Balaban’s has been a Trustee and President of the Society for Magnetic Resonance in Medicine/ International Society for Magnetic Resonance in Medicine, 1994-1996; and Trustee and President of the Society for Cardiovascular Magnetic Resonance 1999-2001. He has also a member of The American Physiological Society, The American Society for Cell Biology, The Society of General Physiologist and The Biophysical Society.

Robert Bao, PhD

Massachusetts General Hospital

Dr. Robert Bao earned his bachelor’s degree in biology at Caltech, where he worked in Henry Lester’s lab studying novel conduction modes of P2X family receptors. He returned to Caltech in 2001 for his Ph.D. in the laboratories of Prof. Steve Quake and Prof. Mel Simon as a Hertz Foundation Fellow, studying DNA polymer mechanics at the single molecule level and calcium signaling dynamics at the single cell level. Since 2008, he has been a postdoctoral research fellow in Vamsi Mootha’s lab at the Massachusetts General Hospital, where he studies novel ways in which human cells alter their metabolism in response to induced dysfunction of the mitochondria.

Salvatore DiMauro, MD

Columbia University Medical Center

Salvatore DiMauro graduated in Medicine in 1963 at the University of Padua, Italy, where he completed his residency in Neurology in 1966. In 1968, he obtained a postdoctoral fellowship to do clinical research in the Department of Neurology at the University of Pennsylvania. In 1974, he became Associate Professor at the Columbia University Medical Center (CUMC). In 1991 he was named Lucy G. Moses Professor of Neurology. Throughout his career, Dr. DiMauro has kept a focused interest on inborn errors of energy metabolism, recognizing unusual patients through clinical observation, and using both biochemical and molecular approaches to define disease entities. He started as an “enzyme hunter” (and in 1973 discovered CPT deficiency, the first defect of fatty acid oxidation in humans) and became interested in the molecular bases of inborn errors of metabolism, especially mitochondrial encephalomyopathies. He has received honorary degrees from the Université de la Mediterranée, Marseille, France and the University of Pisa, Italy. Since 2002 he is a member of the Institute of Medicine.

Steven Gross, PhD

Weill Cornell Medical College

Costas A. Lyssiotis, PhD

Weill Cornell Medical College

Dr. Costas A. Lyssiotis obtained his bachelor’s degree in chemistry and biochemistry from the University of Michigan and his PhD in chemical biology at The Scripps Research Institute in La Jolla, CA. In 2010, he joined the laboratory of Prof. Lewis C. Cantley at Harvard Medical School as the Amgen fellow of the Damon Runyon Cancer Research Foundation. He is currently a Pancreatic Cancer Action Network Pathway to Leadership Postdoctoral Fellow in Prof. Cantley’s laboratory, now at Weill Cornell Medical College. His research is focused on understanding the biochemical pathways and metabolic requirements that enable pancreatic tumor growth and, in particular, how this information can be used to design targeted therapies to treat this dreadful disease. Among his many contributions, he demonstrated that pancreatic cancers are addicted to glucose and glutamine and use these nutrients in previously undescribed pathways to make DNA and to generate free radical-combating antioxidants, respectively. For this work, he was recently awarded a Dale F. Frey Award for Breakthrough Scientists.

Jared Rutter, PhD

University of Utah School of Medicine

Dr. Jared Rutter is a Professor of Biochemistry at the University of Utah where he has been on the faculty since 2003. His laboratory employs a wide array of technologies to enable discovery related to metabolic control as well as fundamental aspects of mitochondrial biology. Dr. Rutter received his PhD from the University of Texas Southwestern Medical Center in 2001, working with Dr. Steve McKnight. After receiving his PhD, he spent 18 months as the Sara and Frank McKnight Independent Fellow of Biochemistry before joining the faculty at the University of Utah.

Hazel H. Szeto, MD, PhD

Weill Cornell Medical College

Dr. Szeto is a Professor of Pharmacology and Director of the Research Program in Mitochondrial Therapeutics at Weill Cornell Medical College. Dr. Szeto has extensive expertise in peptide-based drug design and preclinical drug development. In 2004, Dr. Szeto made the seminal discovery that certain water-soluble aromatic-cationic tetrapeptides readily penetrate cells and concentrate in the inner mitochondrial membrane. She has discovered that these peptides selectively target cardiolipin on the inner mitochondrial membrane, promote electron transfer through cytochromce c, enhance ATP production and reduce ROS generation. These mitochondria-targeted peptides have been shown to protect mitochondrial structure and restore bioenergetics in preclinical models of age-associated complex diseases, including cardiorenal diseases, metabolic diseases, neurodegenerative diseases, skeletal muscle weakness, and neuropathic pain. Dr. Szeto founded Stealth Peptides International in 2006 to take these first-in-class cardiolipin therapeutics to clinical trials. The first drug candidate (Bendavia) is currently undergoing Phase 2 clinical trials for acute cardiorenal ischemic injury, diabetic retinopathy, heart failure, and mitochondrial diseases. Dr. Szeto remains a full-time faculty member at Weill Cornell Medical College while serving as Scientific Consultant to Stealth Peptides. She received her M.D. and Ph.D. in Pharmacology from Cornell University Medical College in 1977.

Benjamin P. Tu, PhD

UT Southwestern Medical Center

Dr. Benjamin P. Tu received his A.B. and A.M. degrees in Chemistry from Harvard College in 1998, where he worked in the laboratory of Dr. James C. Wang. He then received his Ph.D. in Biochemistry and Biophysics from the University of California, San Francisco in 2003 under the mentorship of Dr. Jonathan S. Weissman. He pursued postdoctoral training under the mentorship of Dr. Steven L. McKnight in the Department of Biochemistry at UT Southwestern Medical Center in Dallas, Texas. He started his own lab in the Department of Biochemistry at UT Southwestern in 2007. His lab is interested in understanding how fundamental cellular processes are coordinated with metabolism.

Sponsors

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Academy Friend

Thermo Fisher

Promotional Partners

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Journal of Alzheimer's Disease

Metabolomics Society

MitoAction

Nature

North Jersey Section American Chemical Society (NJACS)

United Mitochondrial Disease Foundation

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Abstracts

Systems Biology of Muscle Mitochondrion
Robert S. Balaban, PhD, Laboratory of Cardiac Energetics, National Heart Lung and Blood Institute

Over wide ranges of workload the heart is capable of maintaining the free energy in high energy phosphates. This metabolic homeostasis is fundamentally dependent on the precise modulation of mitochondrial oxidative phosphorylation (MOP) to match work related ATP hydrolysis.. Screening tools have permitted the detailed information on the gene and protein expression, enzyme activity, post-translational modifications (PTM) and metabolite alterations associated with adjusting MOP to specific needs under normal and disease states. Studies between ventricles and across species reveal that the protein content, or program, from DNA sets the maximum MOP capacity. Interestingly the ratio of MOP capacity and myofibril content is constant across ventricles and species with similar maximum workloads but ~10 fold differences in resting workload, implying a optimized balance mitochondrial and myofibril volumes in the heart cell. Acute regulation of MOP is modulated via PTM and metabolite alterations. Calcium activation of dehydrogenases (DH) has been proposed as one of the major regulatory sites of MOP; however, detailed analysis reveals that DH activation alone is inadequate to explain the metabolic homeostasis. Evidence is building that the entire MOP cascade is acutely regulated during work transitions. Using native gels and optical methods to screen MOP Complex activity, Complex IV and V Vmax correlated with overall cardiac workloads across species and during work transitions. Optical studies of the entire reaction cascade in intact mitochondria reveal that all of the Complexes are modulated by calcium as well as challenges such as reperfusion injury. These data suggest that PTM are coordinating MOP Complex activity in order to maintain the cytosolic energy metabolic homeostasis. Finally, genetic knockout experiments have questioned the role of facilitated diffusion of oxygen (myoglobin knockout) and phosphate metabolites (creatine kinase and “creatine” knockout) to contribute to the metabolic homeostasis in the normal function in the mouse. These observations bring into question the reaction-diffusion models in muscle, implying that the fine structures of the cells and mitochondria should be re-examined. Using state of the art 3D electron microscopy techniques the reaction-diffusion model with regard to the distribution of the energy converted by mitochondria is being re-examined.

The Metabolic Response to Mitochondrial Dysfunction in Human Cells
Xiaoyan Robert Bao, PhD, Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA;Department of Systems Biology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA

Mitochondrial defects are associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as diabetes and neurodegeneration. In yeast, genetic “retrograde” signaling programs have been identified that reroute metabolism to promote cell survival in the face of mitochondrial dysfunction. To characterize how human cells alter their metabolism in response to mitochondrial dysfunction, we systematically characterized metabolite changes following a reversible model of mitochondrial dysfunction. We have performed global metabolic profiling on the cell extracts and media during this perturbation. In this talk, I will present the results from the analysis as well as ongoing experiments aimed at determining whether these changes are simply reactive to mitochondrial stress, or perhaps adaptive, allowing them to survive in the face of the mitochondrial stress.

Overview of Mitochondrial Disorders
Salvatore DiMauro, MD, Department of Neurology, Columbia University Medical Center, New York, NY

After a brief historical background spanning the “pre-molecular era” (1962-1988, the past), I will review the great progress and the many still unsolved problems of the “molecular era” (1988-present). On the “progress” ledger, we have arrived at a rational genetic classification of the mitochondrial diseases, separating those due to mutations in mitochondrial DNA (mtDNA) from those due to mutations in nuclear DNA (nDNA). Each group can be subdivided into subgroups: thus, mtDNA-related disorders can be due to mutations affecting mitochondrial protein synthesis or individual protein-coding genes. Mutations in nDNA can affect subunits of the respiratory chain (“direct hits”), assembly proteins (“indirect hits”), factors involved in mtDNA transcription or translation, the phospholipid composition of the inner mitochondrial membrane (IMM), mitochondrial dynamics (fission, fusion, mitophagy), or factors controlling mtDNA quantity and quality (“maintenance”). This classification does not have merely taxonomic value but it also portends major clinical presentations and it poses different therapeutic challenges. Disorders due to defects of mtDNA maintenance are especially interesting because their target is the polyploid mtDNA, which results in overlapping features of mendelian and mitochondrial genetics. The advent and wide application of next-generation sequencing technologies to mitochondrial diseases has revealed nuclear genes encoding “unsuspected” mitochondrial proteins or the association of nuclear genes encoding known mitochondrial proteins with unexpected clinical syndromes. On the “problems” ledger, there are numerous items, including the following: (1) what is the pathogenic basis of the clinical heterogeneity of mtDNA-related disorders? (2) what determines the individual variability and the tissue specificity of homoplasmic pathogenic mtDNA mutations? (3) are mtDNA-related diseases preventable by mitochondrial replacement in the zygote? (4) in the absence of easily obtainable “mitomice,” are we likely to develop effective therapies for mtDNA-related diseases any time soon? (5) are there promising therapies for mendelian mitochondrial diseases (CoQ10 supplementation in primary CoQ10 deficiencies; allogeneic stem cell transplantation in MNGIE; gene therapy)?

Profiling Identifies an Essential Role for Huntingtin Protein in Mitochondrial Respiration and Metabolism

Steven Gross, PhD, Weill Cornell Medical College

Mutations in the Huntington locus (htt) have devastating consequences. Whereas gain-of-polyglutamine repeats in the N-terminal segment of Htt protein is the recognized cause of Huntington’s disease (HD), the function of wildtype Htt protein remains completely unknown. An obstacle to discovering the function of Htt is that htt-/- mutants display very early embryonic lethality, precluding phenotypic analysis. Notwithstanding, pleuripotent htt-/- murine embryonic stem cells (mESCs) are viable and thus amenable to study by metabolomic and cell biological approaches. Taking advantage of mESCs to shed light on Htt protein functions, untargeted metabolite profiling was performed to compare the levels of more than 3,700small molecules in three syngeneic cell lines that differ only in their htt genotype: wildtype (Htt-Q7/7), htt-/-, and poly-glutamine extended (Htt-Q140/7). While Htt-Q140/7 cells do not show major differences from wildtype mESCs in terms of cell bioenergetics, we observed extensive metabolic and bioenergetic aberrations in htt-/- mESCs, including: (i) complete failure of mitochondrial ATP production, despite preservation of the mitochondrial membrane potential; (ii) near-maximal glycolysis rate, with little or no glycolytic reserve; (iii) marked ketogenesis; (iv) depletion of all intracellular NTPs; (v) accelerated purine biosynthesis and salvage; and (vi) loss of mitochondrial structural integrity. Together, these findings demonstrate that Htt is critical for the maintenance of mitochondrial structure and function from the earliest stages of embryogenesis, providing a molecular explanation for early lethality in htt-/- embryos. Chronic neurodegenerative conditions are emerging as a common consequence of gene mutations associated with perturbed mitochondrial metabolism and activities.

Pancreatic Cancer Depends on a Non-Canonical Glutamine Metabolism Pathway
Costas A. Lyssiotis, Department of Medicine, Weill Cornell Medical College

Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts. Among these addictions is an increased utilization of the amino acid glutamine (Gln) to fuel anabolic processes. Recently, we reported the identification of a non-canonical pathway of Gln utilization in human pancreatic cancer cells that is required for tumor growth. While most cells utilize glutamate dehydrogenase (GLUD1) to convert Gln-derived glutamate (Glu) into α-ketoglutarate (αKG) in the mitochondria to fuel the tricarboxylic acid cycle, pancreatic cancer cells rely on a distinct pathway that integrates the mitochondrial and cytosolic aspartate aminotransferases GOT2 and GOT1. By generating αKG from Glu (in conjunction with the conversion of oxaloacetate into aspartate), GOT2 fuels anaplerosis in place of GLUD1. The Asp created is released into the cytosol and acted on by GOT1. This is subsequently used through a series of reactions to yield cytosolic NADPH from malic enzyme. Importantly, we have demonstrated that pancreatic cancers are strongly dependent on this series of reactions to maintain redox homeostasis which enables proliferation. Herein, I will discuss the subcellular compartmentalization and consequences of the aforementioned reactions on pancreatic cancer metabolism. We have also investigated the essentiality of this pathway in other contexts and find that pancreatic cancers have a uniform and unique reliance on this pathway, which may provide novel therapeutic approaches to treat these refractory tumors.

Functionalizing the Unannotated Mitochondrial Proteome
Jared Rutter, Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT

Mitochondria are dynamic and complex organelles that play a central role in all aspects of biology, including energy production, intermediary metabolism, and apoptosis. These broad cellular functions also place mitochondria as a central player in human health. Mitochondrial dysfunction is associated with a wide range of diseases, including cancer, type 2 diabetes, and most neurodegenerative disorders. As a result of these wide-ranging critical activities, many efforts have focused on identifying and characterizing the mitochondrial proteome, with over 1,000 proteins identified to date in mammals. Remarkably, however, roughly one-quarter of these proteins remain essentially uncharacterized. These include many proteins that are highly conserved throughout eukarya, a strong indication that they perform a fundamentally important function. Our studies of a handful of these uncharacterized mitochondrial conserved proteins support this proposal, revealing new roles for these proteins in critical aspects of mitochondrial function and, in two cases, providing new human disease genes. One of these recent discoveries provided the first molecular identification of the protein complex that is necessary and sufficient for mitochondrial pyruvate entry. We have made progress in understanding the biochemical mechanisms governing the activity and structure of this complex and its role in human disease. We have also identified additional proteins with new functions, including mitochondrial protein quality control, lipid synthesis and mitochondrial ETC complex and supercomplex assembly. Our goal in this research is to provide a new understanding of the biochemical and cellular function of each conserved uncharacterized mitochondrial protein, determine how they contribute to normal mitochondrial activity and human disease.

Clinical Development of The First Cardiolipin Therapeutic for Diseases Associated with Mitochondrial Dysfunction
Hazel H. Szeto, MD, PhD, Department of Pharmacology, Weill Cornell Medical College, New York, NY

A decline in energy is common in aging, and the restoration of mitochondrial bioenergetics may offer a common approach for the treatment of numerous age-associated diseases. Cardiolipin is a unique phospholipid that is exclusively expressed on the inner mitochondrial membrane where it plays an important structural role in cristae formation and the organization of the respiratory complexes into supercomplexes for optimal oxidative phosphorylation. Cardiolipin peroxidation and depletion have been reported in a variety of pathological conditions associated with energy deficiency, and cardiolipin has been identified as a target for drug development. This presentation will focus on the discovery and development of the first cardiolipin therapeutic. SS-31 (Bendavia) is a tetrapeptide known to selectively target the inner mitochondrial membrane. SS-31 binds selectively to cardiolipin via electrostatic and hydrophobic interactions. By interacting with cardiolipin, SS-31 protects cristae architecture, promotes ATP synthesis, and reduces electron leak and ROS production. Bendavia represents a new class of compounds that can re-charge the cellular powerhouse and restore bioenergetics and is currently being evaluated in several Phase 2 clinical trials.

How Yeast Cells Decide to Make Mitochondria
Benjamin P. Tu, University of Texas Southwestern Medical Center, Dallas, TX

Mitochondria play critical roles in cellular energy metabolism, signaling, and survival. The biogenesis of new mitochondria must be properly regulated according to the needs of the cell. In Saccharomyces cerevisiae, mitochondrial biogenesis is repressed in the presence of abundant glucose. Under such conditions, budding yeast cells prefer a highly glycolytic metabolism. Upon glucose depletion or switch to non-fermentable fuels, yeast cells induce mitochondrial biogenesis to increase their capacity for oxidative catabolism of carbon sources. However, nuclear-encoded genes required for mitochondrial biogenesis are not transcriptionally silent under glucose-rich conditions. They are transcribed but then rapidly degraded. While several transcription factors have been implicated in the transcriptional regulation of genes important for mitochondrial biogenesis, an RNA-binding protein, which is not a canonical transcriptional factor, has also been linked to the regulation of such genes. We investigated how this RNA-binding protein is involved in the post-transcriptional regulation of mRNA transcripts important for mitochondrial biogenesis, which has revealed an exquisite logic underlying the regulation of this class of genes. Studies of this fundamental process have also led to a number of surprises that could help improve our understanding of the etiology of certain neurodegenerative diseases.

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