MITO INNOVATION SCHOLARS 2021
The MITO Innovation Scholars in Mitochondrial Health and Medicine represent a growing community of brilliant minds at the forefront of advancing mitochondrial health and medicine. As recipients of the prestigious MITO2i graduate scholarship, these scholars are dedicated to unraveling the mysteries of mitochondrial function and its profound impact on human health. United by a common passion for innovation, they form a dynamic network of trailblazers committed to pushing the boundaries of mitochondrial research.
Click below to learn more about this year’s funded projects!
Aadil Ali
Manipulation of Organ temperature and Metabolism for the Extension of Donor Lung Preservation Times
Marcelo Cypel, Institute of Medical Sciences, UofT, University Health Network
David Bodenstein
Novel approaches to eliminate mutant mitochondrial DNA and transplantation in patient-derived induced-pluripotent stem cells
Ana Andreazza, Department of Pharmacology and Toxicology, University of Toronto
Thomas Hurd, Department of Molecular Genetics, University of Toronto
Swathi Jeedigunta
Determining the role of PolG1 in eliminating deleterious mitochondrial DNA from the female germline
Thomas Hurd, Department of Molecular Genetics, University of Toronto
Ana Andreazza, Department of Pharmacology and Toxicology, University of Toronto
Sanna Masud
Mapping the genetic interactions of TAZ: towards a functional wiring diagram of the mitochondrion
Jason Moffat, Department of Molecular Genetics, University of Toronto
Charlie Boone, Department of Molecular Genetics, University of Toronto
Aleksandra Marakhovsakaia
Establishing a novel role of mental illnesses associated gene, Fxrlin regulation of mitochondrial function in cortical neurons. Potential relevance for the mitochondrial function dysregulation in psychiatric disorders
Martin Beaulieu, Department of Pharmacology and Toxicology, University of Toronto
Peter McPherson, Department of Pharmacology and Toxicology, University of Toronto
Mohamed Ariff Iqbal
The importance of mitochondrial dynamics in maintenance of neural stem cell function
Ruth Slack, Cellular and Molecular Medicine, University of Ottawa
MITO2i extends heartfelt gratitude to Thomas Zachos for his unwavering support of MITO2i and the Graduate Student Scholarships. Through the generous contributions of the Zachos Chair, collaborative research partnerships, and the dedication of donors, MITO2i can sustain its mission of fostering groundbreaking research and providing invaluable funding opportunities for emerging scholars in mitochondrial health and medicine. Your support ensures that promising minds have the resources they need to advance crucial research in this vital field. Thank you, Thomas Zachos, for your ongoing commitment to mitochondrial innovation and scholarship.
FUNDING PARTNERSHIPS
MITO2i Graduate Student Scholarships of 2022, 2023, and 2024 were funded in part by:
The Hospital For Sick Children (SickKids)
SickKids, is Canada’s foremost pediatric research hospital. They provide child and family-centred care, facilitate scientific advancements, and are a leader in mitochondrial health research.
The University Health Network
The University Health Network (UHN), Canada’s largest health research organization and part of the University of Toronto, plays a pivotal role in facilitating collaborative research with Mito2i.
Sunnybrook Health Sciences Centre
Sunnybrook is Canada’s largest trauma and veterans’ center. Fully affiliated with the University of Toronto, Sunnybrook collaborates with Mito2i in supporting groundbreaking research.
Unity Health Toronto
Unity Health consists of three locations, St. Joseph’s Health Centre, St. Michael’s Hospital, and Providence Healthcare. Affiliated with the University of Toronto, Unity Health serves a diverse population in the Greater Toronto Area.
Aadil Ali
Manipulation of Organ temperature and Metabolism for the Extension of Donor Lung Preservation Times
Marcelo Cypel, Institute of Medical Sciences, UofT, University Health Network
The ability to preserve lungs prior to the time of transplantation has made lung transplantation a clinical reality for those with end-stage lung disease. Currently. lung preservation is performed by flushing the organ with an organ-specific solution. and subsequently storing the organ on ice where it rests at approximately 4’C. Using this approach. preservation times are limited to clinical times of approximately 6-8 hours. Longer preservation times will allow for the overcoming of geographical hurdles faced in organ donation. allow for more optimized donor and recipient matching. and progress lung transplantation towards a semi-elective procedure. Previous reports have shown increased mitochondrial degeneration during prolonged cold storage periods. with an association of worsening graft function. In this project. we aim to explore the specific role of organ temperature during lung preservation on mitochondrial health during the preservation period. with hopes of optimizing the current temperature being used to store lungs. With these findings. we further hope to explore new therapeutic approaches of mitochondrial protection during the cold preservation period such as mitochondrial transplantation and anti-oxidative metabolite preservation solution supplementation
Keywords: Lung transplantation, Lung preservation, Organ storage, Preservation times, Organ donation, Mitochondrial degeneration, Graft function, Mitochondrial transplantation, Antioxidative metabolite preservation solution
David Bodenstein
Novel approaches to eliminate mutant mitochondrial DNA and transplantation in patient-derived induced-pluripotent stem cells
Ana Andreazza, Department of Pharmacology and Toxicology, University of Toronto
Thomas Hurd, Department of Molecular Genetics, University of Toronto
Currently, treatments for mitochondrial dysfunction/disease are limited to antioxidants and compounds targeting specific mitochondrial proteins. however. an emerging approach is the transplant of freshly isolated mitochondria to injury sites. The use of mitochondrial transplants presents several challenges. including the need to identify autologous mitochondria with low levels of mitochondrial DNA (mtDNA) mutations. Therefore,the overall objective of this study is to identify and optimize novel protocols for autologous mitochondrial transplantation in patient-derived induced- pluripotent stem cells (iPSCs). Specifically. we will: (2) Define the best method to reduce or eliminate mutant mtDNA in patient-derived iPSCs: and (2) Establish an efficient and stable mitochondrial delivery method. To date. we have finalized the mitochondrial isolation protocol and are in the process of optimizing the reintroduction of isolated mitochondria into po cells lacking mtDNA.
Keywords: Mitochondrial dysfunction/disease, antioxidants, mitochondrial transplantation, patient-derived induced-pluripotent stem cells (iPSCs), mutant mtDNA, mitochondrial isolation protocol
Swathi Jeedigunta
Determining the role of PolG1 in eliminating deleterious mitochondrial DNA from the female germline
Thomas Hurd, Department of Molecular Genetics, University of Toronto
Ana Andreazza, Department of Pharmacology and Toxicology, University of Toronto
Mitochondrial DNA (mtDNA) is indispensable as it encodes components essential for ATP production. Despite its importance. limited recombination and repair mechanisms result in high rates of mutations in mtDNA which contributes to disease. Unfortunately, most tissues are incapable of selectively recognizing and degrading mutant mtDNA. The female germline. the tissue which gives rise to eggs. is unique. in that it is capable of selectively eliminating mutant mtDNA We aim to uncover the mechanism through which the germline does this in order to manipulate these processes to eliminate mutant mtDNA from diseased tissues. We have identified a number of proteins that play a critical role in eliminating mutant mtDNA from the germline and are currently determining mechanistically how they work together to selectively eliminate mutant mtDNA.
Keywords: Mitochondrial DNA (mtDNA), ATP production, Recombination, Repair mechanisms, Mutant mtDNA elimination, Diseased tissues
Sanna Masud
Mapping the genetic interactions of TAZ: towards a functional wiring diagram of the mitochondrion
Jason Moffat, Department of Molecular Genetics, University of Toronto
Charlie Boone, Department of Molecular Genetics, University of Toronto
Genetic interactions (GI) occur when mutations in multiple genes combine to generate an unexpected phenotype. and aid in our understanding of genotype-to-phenotype relationships in both health and disease. By investigating Gl’s, we can map functional relationships between genes that can be used for identifying genetic elements involved in biological processes and disease. elucidate gene function. and discover therapeutic targets. The disease that has become a driver of my interest in how GI’s involving two or more genes can contribute to an individual’s disease phenotype is Barth Syndrome. rooted in mutations in the gene TAZ There is extreme variability observed in Barth Syndrome patients even though one gene is responsible for this disease. suggesting that there are modifier genes or additional variants of TAZ that could be involved. My project aims to generate the first genetic interaction profile of the TAZ gene using a highly sensitive genome- wide CRISPR/Casg screening platform. In parallel this project aims to generate the first comprehensive reference genetic interaction map of the mitochondria in human cells. exploring relevant disease alleles and GI’s involved in both physiological and pathological conditions.
Keywords: Genetic interactions (GI), Genotype-to-phenotype relationships, Gene function elucidation, Therapeutic targets discovery, Barth Syndrome, TAZ gene mutations, Modifier genes, CRISPR/Cas9 Mitochondrial genetic interaction map
Aleksandra Marakhovsakaia
Establishing a novel role of mental illnesses associated gene, Fxrlin regulation of mitochondrial function in cortical neurons. Potential relevance for the mitochondrial function dysregulation in psychiatric disorders
Martin Beaulieu, Department of Pharmacology and Toxicology, University of Toronto
Peter McPherson, Department of Pharmacology and Toxicology, University of Toronto
The project is designed to establish a link between psychiatric illnesses risk gene FXR1 and mitochondrial function that could explain mitochondrial malfunction in the patients with disorders such as schizophrenia and bipolar disorder. Firstly. we are planning to establish a molecular phenotype of mitochondria using cell culture models and CRISPR-Casg approach to target the gene of interest. Secondly. we will pursue a similar approach to knockout the gene of interest in cortical neurons of adult mice using viral delivery to check for mitochondrial phenotype. And at last. we plan to test if the protein of interest exhibits protective function against oxidative stress in mitochondria.
Keywords: Mental illnesses, Gene regulation, Mitochondrial function, Cortical neurons, Psychiatric disorders, Schizophrenia, Bipolar disorder, Molecular phenotype, Cell culture models, CRISPR-Cas9
Mohamed Ariff Iqbal
The importance of mitochondrial dynamics in maintenance of neural stem cell function
Ruth Slack, Cellular and Molecular Medicine, University of Ottawa
Strong evidence suggests a key role for adult neurogenesis in tissue regeneration and cognitive function. Understanding the regulation and persistence of neural stem cells (NSC) in the adult brain is critical for real-life application in neurodegenerative diseases. Our group has shown that mitochondrial function plays a pivotal role in regulating NSC and cognitive function. Our goal is to identify how mitochondrial dynamics and metabolism regulate neurogenesis and learning and memory. Unbalanced mitochondrial dynamics results in mitochondrial fragmentation. which is seen during aging and at an accelerated rate in neurodegenerative diseases Optic atrophy 1 (OPA1. a gene implicated in Parkinson’s Disease and Dominant Optic Atrophy) facilitates mitochondrial fusion and regulates energetics We use Opat inducible knockout in mouse NSCs to model accelerated aging and neurodegeneration. We show that Opai loss leads to mitochondrial dysfunction which induces a cascade of cellular stress response that regulates cell survival at the expense of NSC proliferation.
This study reveals how mitochondrial dysfunction. typical of neurodegenerative diseases alters NSC fate decisions and identifies new regulatory targets by which to enhance mitochondrial function in the context of neurodegeneration. Modulating such stress conditions posed here opens new avenues in neurodegenerative disease therapeutic strategies
Keywords: Mitochondrial dynamics, Neural stem cell function, Adult neurogenesis, Tissue regeneration, Cognitive function, Neurodegenerative diseases, Mitochondrial function, Learning and memory, Mitochondrial fragmentation, Aging, Parkinson’s Disease