Mitochondria in the Pathogenesis of Lung and Sleep Disorders Workshop

Key Information

On December 1-2, 2022, the National Heart, Lung, and Blood Institute (NHLBI), of the National Institutes of Health (NIH), virtually hosted a workshop titled "Mitochondria in the Pathogenesis of Lung and Sleep Disorders". The workshop aimed to convene basic, translational, and clinical scientists to thoroughly examine the current research on pathobiological mechanisms involving mitochondrial dysfunction in lung and sleep disorders, as well as potential diagnostic and therapeutic strategies. The primary goal was to identify critical knowledge gaps and short-term research priorities that could have the greatest impact on the field.

Background

Mitochondria are essential cellular organelles widely recognized for their role in energy production. However, recent studies have highlighted their critical functions in a broad range of additional biological processes, such as biosynthesis, ion homeostasis, innate immunity/inflammation, epigenetic modification, signaling, cell survival and proliferation, and stem cell/adult progenitor cell maintenance and fate. Recent findings suggest that mitochondrial abnormalities, which accumulate with aging and differentially affect distinct cell types, may act in many ways to disrupt lung cellular behavior and compromise the resilience of this complex organ. Yet, there is still limited knowledge about the contributions of mitochondrial dysfunction to the pathogenesis of lung and sleep disorders.

Challenges and Goals

The intricate and varied lung cell types and structures, along with the multitude of causes and risk factors for respiratory and sleep disorders, and the diversity of mitochondrial functions, present significant challenges to this field. The objectives of this workshop were to review recent research on pathobiological mechanisms, as well as diagnostic and therapeutic strategies for mitochondrial dysfunction in lung and sleep disorders, and to pinpoint critical knowledge gaps, emerging opportunities, and research priorities that have the potential to revolutionize this field.

Thematic Areas of Discussions and Findings

The workshop concentrated on the following thematic areas. Presentations were followed by breakout group discussions aimed at recognizing knowledge gaps, research opportunities, and priorities.

Mitochondrial DNA Damage, Mutation, and Dysfunction

Extensive discussions in this thematic area centered around how to mine and analyze mitochondrial (mtDNA) and genomic DNA databases, such as those in the Trans-Omics for Precision Medicine (TOPMed) program, to correlate with disease phenotypes; how to accurately assess mtDNA mutation/damage/mitochondrial dysfunction; how mitochondrial dysfunction contributes to the pathogenesis of lung and sleep disorders; and how to restore or correct mtDNA damage or mitochondrial dysfunction. Participants recognized priority areas, including the need to define causal relationships between mtDNA mutation/damage/mitochondrial dysfunction and disease phenotype and to better understand the cascades of events in pathogenesis. They also highlighted the need to incorporate mitochondrial genome (inherited haplotypes and somatic mutations) in genome-wide association studies (GWAS), and the importance of validating study results. The group also stressed the necessity of determining thresholds of mtDNA mutation or other mtDNA damages, such as oxidative damage, base oxidation, deletions, that can cause disease phenotypes and to explore how pathways regulate mtDNA replication to restore mtDNA integrity. Additionally, there is an unmet need for clinical trials to investigate the link between mitochondrial mutations and sleep disorders, focusing on incidence and treatment options/benefits.

Mitochondria in Immune Regulation

Topics presented and discussed in this thematic area included how cell-free mtDNA and other damage-associated molecular patterns (DAMPs) activate inflammatory pathways, how insults such as cigarette smoking impair mitophagy pathways and thereby enhance inflammation, and how mitochondrial dysfunction in immune cells or lung structural cells might contribute to the aberrant cell senescence and death. Group members voiced the need to decipher specific mitochondrial DAMPs (mtDNA, mtRNA, and others) that modulate innate immune and inflammatory responses in disease-specific contexts. They also emphasized the need to investigate cell-type-specific mitochondrial function and the potential cell-type-specific impact of interventions, as well as understanding the role of mitochondria in pathogen defenses and responses of specific lung cell types.

Mitochondrial Homeostasis and Dynamics

The main topic of this group was mitochondrial fusion/fission and mitophagy and how these processes, in connection with signaling pathways or environmental insults, contribute to development of lung diseases by altering cell proliferation, senescence, survival, and regeneration. Modulating mitochondrial dynamics and homeostasis as potential therapeutic approaches were also extensively discussed. The breakout group described a need to better understand the physical and functional interactions of mitochondria with other cellular organelles, such as the nucleus, lysosomes, and peroxisomes. They also emphasized the need to clarify how dysregulation of mitochondrial biogenesis and quality control, dynamics, and distribution results in cell or tissue damage and diseases, to identify the specific sites of mitochondrial damage, and to develop targeted therapies to correct these defects.

Mitochondrial Metabolites and Translational therapy

Topics covered in this thematic area included the need for metabolomic signatures associated with mitochondria to aid disease diagnosis and prognosis, as well as the development of novel therapeutic approaches to restore mitochondrial function, such as mitochondria-targeted drugs or transfer and restoration of mitochondrial functions using extracellular vesicles. Participants recognized the need to investigate lung mitochondrial function in a physiological context, generate new tools to measure and manipulate metabolic and other signals, and develop biomarkers of altered mitochondrial function (such as metabolites, circulating mtDNA, and mitokines) in lung diseases. They also emphasized the broad potential value of mitochondria-targeted therapeutic strategies.

Special Topics: Cell-type Specific Mitochondrial Analyses and Mitochondria in Lung Cell Fate Determination

Presentations and discussions on these two special topics included single-cell mtDNA sequencing and cell type-specific analyses of mitochondrial function and cellular metabolism, as well as the role of mitochondrial pathways in cell fate determination in development and regeneration. This group described the critical need to examine mtDNA mutations/damage and mitochondrial dysfunction in a cell type-specific manner and with regard to a particular physiological context. They also discussed an untapped opportunity to understand the role of mitochondria in adult progenitor cell survival, maintenance, and differentiation in lung aging and regeneration.

Conclusion

Although groups working on different thematic areas considered specific knowledge gaps and research priorities, several general themes emerged across all breakout sessions. These included the importance of obtaining a comprehensive understanding of mtDNA mutation/damage, mitochondrial dysfunction, homeostasis, dynamics, and associated pathways in diseased lungs and to do this in a cell type-, disease phase-, gender-, and age-specific manner. There is an unmet need to define causal relationships and the cascade of events in pathogenesis that lead to disease phenotype. Participants also identified a need for mechanisms to stimulate multidisciplinary collaboration.

Workshop Participants

Chairs

• Mark Gillespie, Ph.D., Professor and Chairman, Department of Pharmacology, University of South Alabama
• Serpil Erzurum, MD, Chief Research & Academic Officer, Cleveland Clinic, Chair, Lerner Research Institute

Speakers

• Stephen Archer, M.D., Head of the Department of Medicine and the C. Franklin and Helene K. Bracken Chair, Queen's University, Canada
• Kewal Asosingh, Ph.D., Scientific Director, Flow Cytometry Core Lerner Research Institute
• Jahar Bhattacharya, MD, Ph.D., Professor of Medicine, Director of Lung Research at the Division of Pulmonary and Critical Care Medicine, Columbia University Medical Center
• Harm Jan Bogaard, MD, Professor, Pulmonary Medicine Department of Pulmonology, Amsterdam Cardiovascular Sciences, De Boelelaan 1117, Amsterdam, The Netherlands
• A. Brent Carter, MD, Professor in medicine and Scientific Director of the Interstitial Lung Disease Program, University of Alabama
• Ian Holt, Ph.D., Ikerbasque Research Professor, BioDonostia Health Research Institute, Universidad de País Vasco, Barrio Sarriena s/n, 48940, Leioa, Bilbao, Spain
• Navdeep Chandel, Ph.D., David W. Cugell, MD, Professor. Professor of Medicine (Pulmonary and Critical Care) and Biochemistry and Molecular Genetics, Northwestern University
• Dr. Heath Gasier, Assistant Professor in Anesthesiology, Duke University
• Valerian Kagan, Ph.D., Professor, Environmental and Occupational Health, Vice Chair of Research, Environmental and Occupational Health, University of Pittsburg
• Min Jong Kang, MD, Ph.D., Associate Professor of Medicine, Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine
• Chunyu Liu, Ph.D., Associate Professor, School of Public Health, Boston University
• Anna Krasnodembskaya, Ph.D., Reader, School of Medicine, Dentistry and Biomedical Sciences, Wellcome Wolfson Institute for Experimental Medicine, UK
• Sadis Matalon, Ph.D. Distinguished Professor and Alice McNeal Endowed Chair of Anesthesiology, Vice Chair and Director, Division of Molecular and Translational Biomedicine, Director, UAB Pulmonary Injury and Repair Center UAB
• Raymond Langley, Ph.D., Assistant Professor at the University of South Alabama, College of Medicine
• Evangelos D. Michelakis, M.D., Canada Research Chair in Applied Molecular and Mitochondrial Medicine University of Alberta, Edmonton
• Ana Lucia Mora, M.D., Associate Director of Lung Research, Professor, Division of Pulmonary, Critical Care and Sleep Sadis Matalon, Ph.D. Distinguished Professor and Alice McNeal Endowed Chair of Anesthesiology, Vice Chair and Director, Division of Molecular and Translational Biomedicine, Director, UAB Pulmonary Injury and Repair Center UAB
• Guido Primiano, M.D., Ph.D., Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
• Marlene Rabinovitch, Dwight and vera dunlevie Professor of pediatric cardiology, Stanford university
• Irfan Rahman, Ph.D., Professor, Environmental Medicine, Medicine (Pulmonary), and Public Health Sciences, University of Rochester Medical Center
• Anuradha Ray Ph.D., UPMC Endowed Chair in Lung Immunology in Medicine. Professor, Department of Immunology, University of Pittsburgh School of Medicine
• Sharon Rounds, MD, Professor of Medicine and of Pathology and Laboratory Medicine at Brown Medical School, Brown University
• Vijay G. Sankaran, MD, Ph.D., Lodish Family Chair in the Division of Hematology/Oncology, Boston Children's Hospital; Associate Professor of Pediatrics, Harvard Medical School
• Gerald Shadel, Ph.D., Professor Molecular and Cell Biology Laboratory, Audrey Geisel Chair in Biomedical Science Salk Institute for Biological Studies
• Sruti Shiva, Ph.D., Professor & Vice Chair for Academics and Equity. University Of Pittsburgh
• Xin Sun, Ph.D., Professor, Department of Cell and Developmental Biology, University of California, San Diego
• Ying Tian, Ph.D., Associate Professor, Department of Cardiovascular Sciences, Center for Translational Medicine, Lewis Katz School of Medicine at Temple University
• Lisa K Torres, MD, Assistant Professor of Medicine, Medicine, Weill Cornell Medical College

Discussants

• Mark T. Gladwin, M.D., Vice President for Medical Affairs, UM Baltimore, and John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine
• Dr. Hongwei Yao, Associate Professor of Molecular Biology, Cell Biology & Biochemistry at Brown University Warren Alpert Medical School
• Dr. M. Naeem Islam Director, Institute of pure and applied biology, Bahauddin Zakariya University, Multan-Pakistan
• Claude Piantadosi, MD, Professor Emeritus of Medicine, Duke University
• Paul T Schumacker, Ph.D., Patrick M. Magoon Distinguished Professorship in Neonatal Research, Professor of Pediatrics, Cell and Developmental Biology and Medicine, Northwestern University
• Dr. Gregory Waypa, Research Associate Professor, Pediatrics, Northwestern University

NHLBI Leads

• James Kiley, Ph.D., Director, Division of Lung Diseases, NHLBI, NIH
• Jining Lu, Ph.D., Program Director, NHLBI, NIH
• Qing Lu, Ph.D., Program Director, NHLBI, NIH