The special issue of Journal of Cell Science (JCS) on the “Cell Biology of Mitochondria” looks to be one of the most comprehensive open series of papers, opinions, perspectives, interviews, reviews and posters on the subject of mitochondria biology, perhaps ever.
This incredibly in-depth examination of mitochondria covers the subject in research, interviews and commentary and does so in what can only be described as a community spirit from the Journal of Cell Science (JCS) a publication of the Company of Biologists, which is “dedicated to supporting and inspiring the biological community.”
A Good Place to Start [Editorial]
The Cell Biology of Mitochondria Special Issue is a collaboration led by Ana J. Garcia-Saez, Max Planck Institute of Biophysics and Heidi McBride, Department of Neurology and Neurosurgery McGill University, guided by Cell Biology Executive Editor Seema Grewal, who has a deep publishing and research biology background. McBride is also a member of the MitoWorld Scientific Advisory Board (SAB).
MitoWorld was so impressed with this collection, enough reading for a month, that the questions arose of how does such an issue come together and how does it stand to help the mitochondrial research world as the subject becomes more popular. To get a sense of this, Executive Editor Seema Grewal answered a few questions.
MitoWorld: What prompted the special issue?
Grewal: JCS has a long and rich history of publishing papers in the field of mitochondrial cell biology; indeed, some of the early papers examining the factors that contribute to mitochondrial fusion and fission were published in JCS. We wanted to remind the community about this, so what better way to do this than to coordinate a special issue on the topic.
MitoWorld: This was a huge undertaking, how did this get going and how long has it taken?
Grewal: We started discussing the idea at the journal’s annual gathering of editors back in February 2024. Heidi and Ana are on the journal’s Editorial Advisory Board and are experts in the field, so the team felt that they would be well-placed to serve as Guest Editors for the issue. After some discussion with them, we decided on the aim, scope and timeline for the special issue. We put out a call for papers in the Spring of 2024 and had an encouraging response from the community, resulting in lots of research articles being submitted for consideration in the special issue. In parallel, we also identified and invited experts from across the field to contribute review-type articles.
MitoWorld: Can you talk about the Journal and its mission and how you are able to put together projects at this scale.
Grewal: JCS prides itself in being a community journal that is published by a not-for-profit publisher (The Company of Biologists) that exists to benefit scientists not shareholders. Coordinating a special issue is hard work, but we’re fortunate to have an in-house team that can support Guest Editors in coordinating the issue, so that they can focus on the science. This team works closely with the Guest Editors to ensure the smooth and efficient handling of articles.
MitoWorld: What do you hope comes from such a publication? Who should be reading this issue?
Grewal: We’re hoping that the issue will inspire the community and stimulate debate and discussion. It contains a range of research and technical articles that showcase the advances in the field. It also contains some in-depth reviews that synthesize the latest findings. We’ve also included some perspective and opinion articles that challenge our view of mitochondria. Finally, we strongly believe that it’s important to highlight the scientists that actually do the work, so the issue includes some interviews with researchers at different career stages. We’re hoping there’s something in the issue for everyone. It’s also worth pointing out that, thanks to our ‘Forest of Biologists’ initiative, we planted 24 trees to represent the 24 peer-reviewed articles published in the issue, so that’s another really positive outcome!
MitoWorld: There is so much material, do you have suggestions on what busy people should concentrate on or how to best use the whole resource.
Grewal: The Opinion piece is a good place to start, as it provides an over-arching view of mitochondria. After that, we suggest that people just bookmark the full table of contents and dip in and out of any reviews or research articles that appeal to them
MitoWorld: What do you hope the take-aways are for the serious reader of this special issue?
Grewal: That we’ve made lots of progress, largely thanks to new technologies…but there’s still so much to learn!
Since the days of van Leeuwenhoek and his microscope, new technologies have allowed researchers to look at life, quite literally, in new ways. As technologies have grown in power, they also increased in cost and complexity, often putting them beyond the means of individual researchers. Many research organizations solved this challenge by developing core facilities in which an expensive instrument is purchased for multiple researchers. Knowledgeable individuals are hired to operate it.
While many research organizations have core facilities, they typically focus on one instrument type (e.g., imaging, bioinformatics, HPLC). At UCLA, Orian Shirihai (professor of medicine and molecular and medical pharmacology) took this concept to the next level by combining advanced technologies of different modalities into a single integrative core. His Mitochondria and Metabolism Core (Core) brings together capabilities in bioenergetics, imaging, and biochemistry to facilitate the study of mitochondria metabolism. The Core may be unique in this comprehensive approach to research on mitochondria.
“Our mission is to empower scientists across academia, biotechnology, and pharmaceutical industries to design, execute, and interpret experiments related to mitochondria and metabolism. By doing so, we aim to accelerate scientific discovery and the development of novel therapies and diagnostics,” said Dr. Shirihai.
The Core comprises three sections. The bioenergetics section, led by Linsey Stiles, features several Seahorse instruments that measure oxygen consumption and extracellular acidification providing readouts of mitochondrial respiratory function, glycolysis, ATP production rates, and other metabolic measurements. The imaging section, led by Cristiane Beninca, has a broad selection of microscopes (brightfield, widefield, confocal, FLIM, and super-resolution microscopes as well as a transmission electron microscope) and techniques to study mitochondrial structure and function (e.g., membrane potential, reactive oxygen species, and NADH measurements, mitophagy flux, mitochondrial and cristae dynamics, organelle interactions) in live and fixed samples. A biochemistry section, led by Lucia Fernandez-del-Rio complements the other sections with enzyme assays, western blots, non-denaturing gels to examine mitochondria supercomplexes, and mtDNA-based assays.
The Core provides an exceptional resource for basic, clinical, and industry researchers who are interested in mitochondria research. It helps in all phases of mitochondrial research from study design to data interpretation. The Core operates on a fee-for-service recharge system, offering a range of options from full-service support to specialized training for autonomous use of advanced equipment, and everything in between.
In recent years, physicians and researchers have come to appreciate the intimate involvement of mitochondrial dysfunction in human disease. The Core provides a unique resource to accelerate research in this critical area. Its value is documented by its broad spectrum of users, including researchers at UCLA and many other organizations, such as CalTech, UC Santa Barbara, and USC.
David Shackelford, PhD (professor of medicine, UCLA), said, “The mitochondrial metabolism and the imaging cores at UCLA have been an incredible resource and been transformative with respect to our research.” Amy Wang, PhD (CEO, Enspire Bio Inc.), added, “The UCLA mitochondria cores are indispensable collaborators and have transformed the direction and focus of our research and were important for informing our scientific strategy.” Clearly, the Core is having an impact on research into metabolism and mitochondria.
For more information about the Core, please visit their website: https://medschool.ucla.edu/research/themed-areas/metabolism-research/metabolism-core.
The Core directors respond to our questions
The UCLA Core seems to be a unique resource for researchers. Are you aware of anyone else who has combined so many powerful technologies to the study of mitochondria?
Providing services as we do, no. We are the only place that can offer services and access to cutting-edge equipment to internal and external scientists in need of the techniques provided. There are certainly places with multiple researchers working in mitochondria research and sharing expertise and access to equipment, but the only way for other researchers to have access to their techniques is through collaborations. In the Core, we offer a fee-by-service system, so anybody can “hire” us to work for them.
Do you plan to add any new resources to your collection (e.g., mass spec, HPLC, new imaging methods)?
At UCLA, additional Core facilities (e.g., Lipidomics, Metabolomics, or Proteomics) are available to clients interested in a multi-omic approach, so we are not considering an expansion in that direction. In the Biochemistry Core, we are working to incorporate mitochondrial DNA (mtDNA)-based assays, such as mtDNA copy number, mutation frequency, or mtDNA nanopore sequencing, into our services. But our portfolio is always expanding as new techniques are constantly in development, and in certain cases, we even work with the clients to develop or improve the techniques they need. Particularly, in the Imaging Core, new dyes, imaging, and analysis techniques are always in development. And in the Bioenergetics Core, new ways to measure mitochondrial function or optimization of different samples are always happening. Once techniques are optimized, they can be added to our portfolio as a service to clients.
Can you describe the general idea of a couple of the studies that the Core has participated in where each of the three sections were involved?
One example is the research paper https://doi.org/10.15252/embj.2022111699. In this project, we started with a Sponsored Research Agreement with a Company that provided us with a compound to be tested. The story progressed into a scientific discovery that was published and even a new technique was developed 10.26508/lsa.202201628
The three sections work very closely together, and we also have researchers with Grants in need of the expertise of all three Cores, and we can work together with them almost as if we were part of their laboratory personnel too.
What would you estimate as the breakdown of your time spent in training, planning experiments and evaluating data, and actual experimenting?
Our top priority is to address the needs of our clients in the best way possible. So, we work together to find the best approach to do so. There are times when we have clients with more knowledge of the techniques needed, and they can be more independent on planning and even running the experiments, so training is just needed in the beginning. Other times, samples are shipped to us, and we are responsible for the whole process until the delivery of results.
How did each of your become interested in the study of mitochondria?
Cristiane Beninca: For me, it was during my PhD that my mentor discovered a new protein localizing at the mitochondria, and since that, everything became mitochondria related.
Lucia Fernandez del Rio: Back in my undergrad days, I joined the Cell Biology Department and started working in a lab that focused on oxidative stress. Since this phenomenon is deeply interconnected to mitochondria, that is where my mitochondria journey started.
Linsey Stiles: I did a rotation focused on the role of mitochondrial fusion and fission in erythropoiesis and knew immediately that I wanted to continue to study mitochondria for my PhD project.
We were honored to hold an interactive session on the work of www.mitoworld.org at the CELL: Multifaceted Mitochondria Symposium in Sitges, Spain, October 27-29.
Three members of the MitoWorld scientific advisory board (Gerry Shadel, Salk Institute for Biological Studies, Mike Murphy, University of Cambridge Mitochondrial Biology Unit, and Heidi McBride, McGill University and I spoke about MitoWorld’s efforts to “mainstream” mitochondria for the public and to the medical sector, pushing also toward a more encompassing mitochondrial science, and beginning a mitochondrial informatics effort.
As a new organization, we were able to hear from the attendees on what they felt was necessary to help the mitochondrial field get more attention and to communicate how essential mitochondria are to health, disease mitigation and solving complex issues from childhood mitochondrial mutation diseases to the issues of aging and age-related diseases, many of which are without therapies.
Symposium attendance was over four hundred mitochondrial researchers from around the world with strong representation from the U.S., UK, Australia, China, Korea, Finland, Germany, Spain and Italy among others. It was also a powerful venue for the interaction between senior researchers and postdocs coming into their positions into the field which is now growing.
Attendees shared with our panel that the public and professional dialog needs to be widened globally. There was an interest in participation with MitoWorld from many of the labs.
The panel invited comments on MitoWorld’s interest in building task forces in various arenas of mitochondrial research mapped to medical practice areas and well-known research subjects. While the task forces idea was well received, the most interest was in finding ways to educate or inform doctors and the medical profession about mitochondria in specific practice areas.
In this case, mitochondria are like the hidden hand in physiology that is not often considered in diagnoses or treatment.
Additionally, there was a sense that the subject of mitochondrial research and eventual practice has to be seen as “across the lifespan,” that mitochondria are ubiquitous and consequential at every stage while, at present, the practice areas are the mutation diseases of early life and the complications of mitochondrial decline in the diseases of aging.
The subject of education, starting in school and college and in medical training, came up several times as a way to anchor mitochondria in culture and eventually in practice. It should be noted that MitoWorld is a project of the R & D nonprofit National Laboratory for Education Transformation, www.NLET.org in California.
We hope the momentum from the Symposium will help build MitoWorld globally.
Mitochondria World is the first step in a process to set up a collaborative and informative mitochondria portal that is designed to service three primary communities: a) patients and clinics through listings and referrals, b) researchers, investigators, labs and institutes to manage a flow of up-to-date research, build working groups and communicate about issues in a single place, and c) to inform and build awareness in the public and among professionals about the significance of mitochondrial research for translation into treatments for diseases and conditions across the entire lifespan, including issues of personal and global health.
Together, as MitoWorld expands, we hope to influence the levels of funding and support for research, collaborations and dialogue beyond seeing mitochondria only through the lens of their individual functions, which has not led to success in developing new drugs for mitochondrial diseases.
By widening awareness and collaborations, we hope we can stimulate more investment for broad-based mitochondrial research to support the difficult path to successful therapies for primary mitochondrial diseases as well other secondary mitochondrial dysfunctions observed in the mostly terminal diseases of aging – cancer, diabetes, neurodegenerative diseases, autoimmune problems and many more.
To further our collaborative mitochondria work, we partner with investigators, institutes and labs across the globe: our mission is to expand our reach as far as possible. We support, publicize, and participate in conferences and symposia like the Cell: Multifaceted Mitochondria Symposium in Spain at the end of October. We schedule lab visits to expand our understanding and coverage of labs and institutes, promoting their work as well. Recent visits to Douglas Wallace’s Lab at Children’s Hospital Philadelphia and at Jared Rutter’s Lab at University of Utah were instructive and we plan to meet with several more investigators by the end of the year.
Critically, our work does not stop at creating awareness and sharing information. As part of an active and still-evolving cellular symbiosis, we believe much is to be learned about how mitochondria regulate health and contribute to many yet untreatable diseases and conditions. A key aspect of our mission is to support leaders in the scientific and medical communities to drive technical advances in mitochondrial biology and medicine. The Scientific Advisory Board of MitoWorld and its staff firmly believe that the time has come to define and name a mitochondrial science and informatics effort that elevates mitochondria from single investigations into categories of research that feed into a general understanding of the basic science of mitochondrial dynamics, systems and complex interactions.
We are open to engaging, presenting and collaborating on both the mitochondrial awareness and basic science fronts. We invite your involvement in our efforts to “mainstream” mitochondria with the public, patient groups, medical practice and across the various research communities to support our collective mission to stimulate more investment and involvement into a broader understanding of the trillions of mitochondria in each of us.