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Targeting
Mitochondrial
Dysfunction
& Toxicity
2015
- ミトコンドリア機能不全・
毒性標的化学会 2015年 -
2015年3月19日 - 2015年3月20日
米国、
マサチューセッツ州
ケンブリッジ、
ハイアット リージェンシー
ケンブリッジ
Targeting
Mitochondrial
Dysfunction & Toxicityの概要
ミトコンドリアの障害や機能不全は、
神経変性状態（筋萎縮性側索硬化症(ALS)、アルツハイマー病、
パーキンソン病など）、
てんかんや自閉症、心臓血管系や
肝臓、腎臓の疾患、がんや糖尿病など
さまざまな病気の重要な要因として
認識されるようになっています。
このように、極めて多くの病気に
幅広い影響を及ぼしている
ミトコンドリアは、
各種治療薬を開発する際の
重要な標的となっています。
また、さまざまな疾病の治療に
用いられる薬剤が
ミトコンドリアにとって
好ましくない毒性を
発揮する場合もあり、
創薬や医薬品開発に携わっている
研究者にとって、
化合物がもたらすこの深刻な副作用を
予測し、防ぐための対策は
極めて重要です。
この学会では、
新たな標的経路や治療法に関する
最新の研究、ミトコンドリアの機能を
理解するという点での画期的な成果、
治療薬開発時にミトコンドリアに対する
毒性を低減あるいは除去するための
方法などが紹介されます。
疾病治療と薬物安全性の向上
この学会で取り上げられる
予定の主なトピック
ミトコンドリアに関する
科学的な知識の発展
ミトコンドリア関連の疾病
と損傷の標的化
ミトコンドリアの標的化と毒性
基調講演
薬物毒性にまつわるミトコンドリア・核間逆行性変性標的特定のための遺伝学的アプローチ
Keshav K. Singh, Ph.D., Departments of Genetics, Pathology, and Environmental Health; Center for Free Radical Biology, Center for Aging and UAB Comprehensive Cancer Center, University of Alabama at Birmingham
ショートコース
薬物誘発性ミトコンドリア毒性
Yvonne Will, Ph.D., Senior Director & Head, Science and Technology Strategy, Drug Safety Research and Development, Pfizer R&D
Kendall B. Wallace, Ph.D., Professor, Biochemistry & Molecular Biology, University of Minnesota-Duluth
Rick G. Schnellmann, Ph.D., Professor, College of Pharmacy, Medical University of South Carolina
Targeting
Mitochondrial
Dysfunction & Toxicity－1日目
3月19日（木）
8:00 am Short Course Registration
9:00 am – 12:00 pm SC1: Drug-Induced Mitochondrial Toxicity*
Chair: Yvonne Will, Ph.D., Senior Director & Head, Science and Technology Strategy, Drug Safety Research and Development, Pfizer R&D
Kendall B. Wallace, Ph.D., Professor, Biochemistry & Molecular Biology, University of Minnesota-Duluth
Rick G. Schnellmann, Ph.D., Professor, College of Pharmacy, Medical University of South Carolina
Mitochondria produce almost all the energy in cells, but also chronically expose the cell to cytotoxic free radicals. Mitochondrial disease and toxicity is a rapidly advancing field and the consequences of mitochondrial impairment should be appreciated by scientists in all disciplines. Numerous widely prescribed therapeutics can undermine mitochondrial function by interfering with DNA replication or expression, and more acutely, by uncoupling or inhibiting oxidative phosphorylation, leading to organ dysfunction and damage. This course will review fundamental concepts of mitochondrial biology and the many different mechanisms by which xenobiotics interfere with mitochondrial function. Both common and novel in vitro screening approaches will be described as well as lectures on mitochondrial dysfunction in the kidney, liver and heart.
* Separate registration required
1:00 Registration for Main Conference
2:00 Chairperson's Opening Remarks
Richard Chapleau, Ph.D., Lead Biochemist, Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance, Henry M. Jackson Foundation for the Advancement of Military Medicine
2:10 KEYNOTE PRESENTATION: Genetic Approaches to Identify Mitochondria-to-Nucleus Retrograde Targets Involved in Drug Toxicity
Keshav K. Singh, Ph.D., Departments of Genetics, Pathology, and Environmental Health; Center for Free Radical Biology, Center for Aging and UAB Comprehensive Cancer Center, University of Alabama at Birmingham
Mitochondria contain multiple copies of mtDNA, varying from 100-1000 copies per cell among different tissues. mtDNA content is reduced by a variety of drugs resulting in toxicity. We have developed genetic approaches to identify nuclear targets involved in retrograde signaling involved in communicating the mitochondrial state to the nucleus, resulting in altered nuclear gene expression, cell physiology, and metabolism mediating drug toxicity.
ミトコンドリアに
関する科学的知識の発展
2:50 Next-Generation Mitochondrial Medicine Platform: Integrated Bioenergetic Phenotyping in Oncology as a Case Study
Anne Diers, Ph.D., Program Leader, Cancer Biology, Berg
A next-generation mitochondrial medicine platform was developed that allows for identification of unique bioenergetic facets that predict cellular responses to stress (e.g., therapeutics, microenvironmental conditions). Using whole-cell integrated energy metabolism parameters coupled with mitochondrial substrate-level oxidation measurements, predictive phenotypic signatures for anti-cancer responses can be identified and molecular adaptive therapy strategies devised. Here, we report the use of this approach to identify the phenotypic signature for sensitivity to BPM 31510, an ubidecarenone-containing formulation that alters mitochondrial metabolism currently in clinical trials for treatment of solid tumors, and highlight the clinical correlates from patients treated with this compound.
3:20 Overview of Mitochondrial Studies in the United States Air Force Research Laboratory: Toxic Impacts of Air Force Materials and Deployment Stresses
Richard Chapleau, Ph.D., Lead Biochemist, Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance, Henry M. Jackson Foundation for the Advancement of Military Medicine
As the powerhouse of the cell, the mitochondria are critically involved in ensuring optimal cellular function and ultimately in cognitive and physical performance. Due to the unique demands placed upon Air Force personnel in theater, the Airman is constantly in a state of high alert and physical exertion. Therefore, it is of critical importance that we have a solid foundational knowledge of the effects of materials and deployment requirements on the mitochondria. Here I provide an overview of the mitochondrial research program within the 711th Human Performance Wing and present recent data and observations investigating the effects of operational stressors on mitochondrial performance.
3:50 Refreshment Break in the Exhibit Hall with Poster Viewing
4:30 A New Answer to an Old Problem: The Energization of Brain Mitochondria is Regulated by Cytosolic Calcium via the "Mitochondrial Gas Pedal" and Does Not Require the Mitochondrial Ca Uptake via the Ca Uniporter
Frank Gellerich, Ph.D., Head, Bioenergetic Laboratory, Neurological University Hospital, Otto-von Guericke-University Magdeburg
In contrast to the classic opinion that the mitochondrial activity is regulated by Ca2+ after its uptake via the Ca2+ uniporter, we found that the energization of mitochondria is realized by the "mitochondrial gas pedal" and is strongly regulated by cytosolic Ca2+ but not by matrix Ca2+. The "mitochondrial gas pedal" realizes the mitochondrial pyruvate supply via oxidizing reactions of pyruvate formation as LDH and GAPDH both generating NADH together with the malate/aspartate shuttle (MAS) or glycero-3-phosphate shuttle (G3PS) both oxidizing NADH. Our model predicts that at sufficiently low Ca2+cyt mitochondria (e.g. in neurons and red muscle) switch into a substrate-limited state preventing dangerous large ROS.
5:00 Mitochondrial Immobilization Mediated by Syntaphilin Facilitates Survival of Demyelinated Axons
Bruce D. Trapp, Ph.D., Department Head, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic
The purpose of this study was to define the roles of mitochondrial volume and distribution in axonal degeneration following acute CNS demyelination. We show that the axonal mitochondrial volume increase following acute demyelination of WT CNS axons does not occur in demyelinated axons deficient in syntaphilin, an axonal molecule that immobilizes stationary mitochondria to microtubules. These findings were supported by time-lapse imaging of WT and syntaphilin-deficient axons in vitro. These results support the concept that syntaphilin-mediated immobilization of mitochondria to microtubules is required for the volume increase of axonal mitochondria following acute demyelination and protects against axonal degeneration in the CNS.
5:30 Welcome Reception in the Exhibit Hall with Poster Viewing
6:30 End of Day 1
Targeting
Mitochondrial
Dysfunction & Toxicity - 2日目
3月20日（金）
8:00 Morning Coffee
ミトコンドリア関連の疾病と
損傷の標的化
8:25 Chairperson's Remarks
Johannes Ehinger, M.D., Mitochondrial Pathophysiology Unit, Lund University
8:30 Adaptive Metabolic Targeting of BPM 31510 for the Treatment of Cancer
Michael Kiebish, Ph.D., Director, Integrative Systems Medicine, Diagnostics, Berg
Mitochondrial dysfunction has long been recognized as a hallmark of cancer, yet there is a paucity of biointelligently designed therapeutics that effectively and selectively reengineer cancer metabolism to effectuate a viable therapeutic strategy. Here, we utilized an adaptive Omic, phenotypic, and biophysical stratification approach to deconstruct the mechanism of action of BPM 31510, a proprietary CoQ10 containing formulation that demonstrates pleotropic effects on diverse cancers. Targeting cancer from a biological, biophysical, physiological, and bioenergetic direction is a prodigious challenge, yet initiating this process from a systems medicine approach allows for therapeutic streamlining toward positive therapeutic effects. Thus, by reengineering the Warburg effect in cancer with strategically designed therapeutics with a multiplicity of downstream effects rather than a single target, we overcome numerous barriers that define the current dogma of targeted therapeutics engaging a systems medicine approach.
9:00 Correcting Abnormal Mitochondrial Dynamics and Mitophagy in Neurodegenerative Diseases
Daria Mochly-Rosen, Ph.D., Professor, Chemical and Systems Biology, Stanford University School of Medicine
Many neurodegenerative conditions are associated with excessive mitochondrial fission and inhibition of mitophagy. However, it is not clear whether these abnormalities in mitochondrial dynamics and removal are the cause of or the result of the pathology. Using a variety of pharmacological tools that we developed rationally, we find that inhibition of mitochondrial fission inhibits neurodegeneration in several models of Parkinson's and Huntington's. A critical role from mitophagy was also identified. The molecular basis for protection from neurodegeneration and the potential utility of our novel pharmacological tools as leads for drug development will be the topic of our presentation.
9:30 Targeting Mitochondrial Dysfunction in Burn Injury
A. Aria Tzika, Ph.D., Director, NMR Surgical Laboratory, Department of Surgery, Massachusetts General Hospital and Shriners Burns Institute
Burn injury represents a significant public health problem in roughly 500,000 people per year in the USA. We probe mitochondrial skeletal muscle dysfunction that occurs in response to burn injury in a preclinical mouse burn model using novel methods. Our studies have the potential for strong clinical relevance with respect to the recovery and management of individuals with burn trauma.
10:00 Coffee Break with Exhibit & Poster Viewing
10:30 Supporting Mitochondrial Function in Cells with Complex I Dysfunction using Cell-Permeable Complex II Substrates: A Potential Novel Therapy for Complex I-Linked Mitochondrial Disease
Johannes Ehinger, M.D., Mitochondrial Pathophysiology Unit, Lund University
Chemically modified mitochondrial complex II substrates with increased cell membrane permeability can support mitochondrial respiration, increase ATP production and uphold mitochondrial membrane potential in cells with deficiencies in complex I-linked mitochondrial metabolism. This new compound class introduces the possibility to pharmacologically support patients with metabolic decompensation due to mitochondrial complex I deficiency, such as children with inborn errors of metabolism.
11:00 Targeting Mitochondria of Cancer Cells: Mitochondria as a Therapeutic Approach
Peng Huang, Ph.D., MD Anderson Cancer Center
In many cancer cells, mitochondria seem dysfunctional, manifested by a shift of energy metabolism from oxidative phosphorylation to active glycolysis and an increase in reactive oxygen species generation. These metabolic changes are often associated with up-regulation of NAD(P)H oxidase. Importantly, the metabolic reprogramming in a cancer cell is mechanistically linked to oncogenic signals. Targeting mitochondria as a cancer therapeutic strategy has attracted much attention in the recent years and multiple review articles in this area have been published. This article attempts to provide an update on recent progress in identification of mitochondria-associated molecules as potential anticancer targets and the respective targeting compounds.
11:30 Sponsored Presentation (Opportunity Available)
12:00 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
ミトコンドリアの標的化と毒性
1:50 Chairperson's Remarks
Padma K. Narayanan, Ph.D., Director, Pre-Clinical/Discovery Toxicology, Amgen
2:00 A Systematic Assessment of Mitochondrial Function Identified Novel Signatures for Drug-Induced Mitochondrial Disruption in Cells
Padma K. Narayanan, Ph.D., Director, Pre-Clinical/Discovery Toxicology
Mitochondrial perturbation has been recognized as a contributing factor to various drug-induced organ toxicities. To address this issue, we developed a high-throughput flow cytometry-based mitochondrial signaling assay to systematically investigate mitochondrial/cellular parameters known to be directly impacted by mitochondrial dysfunction: mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (ROS), intracellular reduced glutathione (GSH) level, and cell viability. Disruptors of mitochondrial function depolarized MMP at concentrations lower than those that caused loss of cell viability, especially in cells cultured in GSM; cellular GSH levels correlated more closely to loss of viability in vitro. Subsequent classification of compounds based on ratios of IC50s of cell viability:MMP determined that this parameter is the most critical indicator of mitochondrial health in cells and provides a powerful tool to predict whether novel small molecule entities possess this liability.
2:30 Screening Small Molecules for Mitofunctional Effects: Implications for Mitochondrial Therapeutics and Mitotoxins
Gino Cortopassi, Ph.D., Professor, Molecular Biosciences, University of California, Davis; CEO, Ixchel PharmA
Mitochondrial disease is a rare/orphan indication, with no approved or effective therapy. Thus screening known FDA-approved drugs for effects on mitochondrial function is a rational approach to shorten the usual time for clinical therapeutic development. Using 4 high-throughput assays we have identified a subset of FDA-approved drugs that target mitochondria. In addition, we have used these assays to screen potential toxicants, and identify known and novel toxicants.
3:00 Targeting Disease-Causing Defects of the Mitochondrial Genome with Engineered Mitochondrial Nucleases
Carlos T. Moraes, Ph.D., Professor, Neurology and Cell Biology, University of Miami
3:30 Inhibitors of Mitochondrial Fission as a Therapeutic Strategy for Diseases with Oxidative Stress and Mitochondrial Dysfunction
P. Hemachandra Reddy, Ph.D., Executive Director and Chief Scientific Officer, Garrison Institute on Aging; Professor of Cell Biology & Biochemistry, Neuroscience & Pharmacology and Neurology Departments, Texas Tech University Health Science Center
Research into mitochondria and cell function has revealed that mitochondrial dynamics is impaired in a large number of aging and neurodegenerative diseases, and in several inherited mitochondrial diseases, and that this impairment involves excessive mitochondrial fission, resulting in mitochondrial structural changes and dysfunction, and cell damage. Attempts have been made to develop molecules to reduce mitochondrial fission while maintaining normal mitochondrial fusion and function in those diseases that involve excessive mitochondrial fission.
4:00 Closing Comments
4:15 Close of Conference
ホテル & 開催地
Hyatt Regency Cambridge
575 Memorial Drive
Cambridge, MA 02139
Hotel Website
Phone: 1-888-421-1442
Discounted Room Rate: $209 s/d
Discounted Room Cut-off Date: February 16, 2015
Please call the hotel directly to reserve your sleeping accommodations. You will need to identify yourself as a Cambridge Healthtech Institute conference attendee to receive the discounted room rate with the host hotel. Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space-and-rate-availability basis. Rooms are limited, so please book early.
Top Reasons to Stay at The Hyatt Regency Cambridge
Complimentary internet in guestrooms
Hotel will provide shuttle to/from Kendall and Harvard Square each evening from 6-10pm
Approximately 15 minutes from Boston Logan International Airport
Sundeck overlooks the beautiful Boston skyline along the Charles River
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