WHO ARE THE MITO INNOVATION SCHOLARS?
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.
Join us in celebrating the MITO Innovation Scholars—a community shaping the future of health through groundbreaking discoveries in mitochondrial science.
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.
Comparing Mitochondrial Dysfunction as a Mediator of Oxidative Stress and Cognition between Vascular Mild Cognitive Impairment and Mild Cognitive Impairment due to Alzheimer’s Disease
Krista L. Lanctôt, Professor, Department of Pharmacology & Toxicology and Psychiatry, University of Toronto
Vascular mild cognitive impairment (VaMCI) and mild cognitive impairment due to Alzheimer’s disease (MCI-AD) are both prodromal stages to dementia. Both conditions are characterized by underlying symptoms such as cognitive decline. Nevertheless, there are several key differences between the two conditions. VaMCI is the mild form of vascular cognitive impairment (VCI). It is defined as early cognitive decline in the presence of cerebrovascular disease, where the cognitive decline is not severe enough to meet dementia criteria. VaMCI has been linked to increased risk of progression to many forms of dementia, particularly vascular dementia. MCI-AD on the other hand, particularly amnestic MCI, is referred as the precursor to Alzheimer’s disease (AD), where it is considered as the transitional state between normal cognition and AD. In both forms of MCI, it is common to identify declines in executive function and higher-order cognition like working memory. It is known that deficits in working memory is one of the most common cognitive impairments, where those deficits involve difficulties in both storing and manipulating information. Although mitochondrial dysfunction and oxidative stress (OS) are associated with AD, these relationships have not been fully explored in VaMCI, and compared to that in MCI-AD.
Mitochondria produce reactive oxygen species (ROS) as byproducts of cellular reactions, and OS occurs when there is imbalance between production of ROS and antioxidants. Unlike nuclear DNA, mitochondrial DNA (mtDNA) is especially susceptible to OS due to its proximity to ROS production, limited DNA repair mechanisms, and lack of protective histones. Consequently, excessive ROS levels can trigger further mitochondrial damage through disruptions of the electron transport chains. This series of events eventually triggers cell death, which results in fragments of mtDNA being released into the blood circulation as circulating cell-free mtDNA (ccf-mtDNA).
Therefore, I aim to 1) Identify if the association of OS levels and working memory at baseline is mediated by ccf-mtDNA in patients with VaMCI vs MCI-AD. 2) Evaluate relationship of baseline ccf-mtDNA and working memory in VaMCI vs. MCIAD patients. 3) Investigate and compare baseline ccf-mtDNA levels in VaMCI vs. MCI-AD patients.
Investigating Hepatocyte Nuclear Factor 4 Alpha as a Central Regulator of Kidney Graft Repair
Dr. Ana Konvalinka- Department of Nephrology, University of Toronto and University Health Network, and Dr. Ana Andreazza- Department of Pharmacology & Toxicology, University of Toronto
Kidney transplantation is the optimal treatment for patients with end-stage kidney disease. Transplantation significantly prolongs life compared to dialysis, incentivizing the use of marginal kidneys to offset organ shortage. Additionally, ischemia-reperfusion injury (IRI) harms all transplanted kidneys and can damage the mitochondria. Normothermic ex vivo kidney perfusion (NEVKP) is a storage method that results in superior graft outcomes when compared to static cold storage. Repairing grafts prior to transplantation would increase the number of viable kidneys, improving graft outcomes. In our previous study, we determined that NEVKP may be repairing kidneys by preserving their mitochondrial protein expression and metabolism. We identified a potential regulator of these mitochondrial proteins, hepatocyte nuclear factor 4a (HNF4A), which may present a novel target for kidney repair. The goal of this project is to determine whether a novel HNF4A agonist, N-trans caffeoyltyramine (NCT), protects kidneys from IRI. My hypothesis is that NCT preserves mitochondrial function and proximal tubular cell viability in vitro and ameliorates kidney injury in a model of bilateral renal IRI in vivo.
Age-selective adolescent amygdala astrocyte susceptibility to chronic delta9-tetrahydrocannabinol (THC)-induced mitochondrial oxidative stress
Dr. Susan R. George, Departments of Medicine, Pharmacology & Toxicology. Dr. Ana C. Andreazza, Department of Pharmacology & Toxicology.
Significant concern exists regarding the rising prevalence of cannabis use among adolescents, given that human brain development remains incomplete until age 25. Increased risk of psychiatric disorders is associated with adolescent exposure to THC, the main psychoactive, cannabinoid type-1 receptor (CB1R)-activating component of cannabis. The amygdala brain region is a key regulator of fear/anxiety behaviours, maturing during adolescence, and is implicated in psychiatric disorders associated with cannabis use. Our laboratory has found increased amygdala oxidative stress and astrocyte-derived neuroinflammation following adolescent exposure to THC, using rodent and primate administration models with proteomic and immunohistochemical techniques. This project will investigate potential THC-activated mitochondrial mechanisms of pro-inflammatory oxidative stress in amygdala astrocytes, and whether this impairs the maturation of neurons. Techniques employed will include in vitro and in vivo calcium imaging, metabolomics, with behavioural testing to investigate functional amelioration with neurometabolic supplementation. Novel mitochondrial astrocyte-neuron crosstalk mechanisms identified may underlie clinical associations between adolescent cannabis use and psychiatric disorders, revealing novel therapeutic targets to reverse enduring harm following adolescent cannabis use.
Protein degradation and mitophagy defects in phospholamban R14d-linked cardiomyopathies.
Dr. Anthony Gramolini, Department of Physiology, University of Toronto
Phospholamban (PLN) regulates cardiac relaxation by inhibiting the function of sarco-endoplasmic reticulum Ca2+ – ATPase, type 2a (SERCA2a)1. In-frame deletion of Arginine 14 in PLN (PLNR14d) has been associated with cardiomyopathy in both human patients and transgenic animal models2-3. Perinuclear aggregates are frequently detected in PLNR14d cardiomyocytes (CM), although the underlying etiology remains unclear4-5. My pilot data has uncovered FK506-binding protein 8 (Fkbp8), a sarcoplasmic-reticulum/mitochondria protein, as a novel PLN-interacting partner. Interestingly, miRNA mediated Fkbp8 reduction results in perinuclear aggregates in cultured mouse neonatal CM6. My project aims to characterize mitochondrial abnormalities in PLNR14d CM, elucidate the role of Fkbp8 in PLNR14d – mediated perinuclear aggregation, and evaluate a novel therapeutic approach for alleviating the cytotoxic effects of PLNR14d in vivo.
Investigating the role of Huntingtin-NEAT1 interactions in regulating mitochondrial bioenergetics in Huntington’s disease.
Prof. Cheryl H. Arrowsmith, Department of Medical Biophysics, University of Toronto/University Health Network (UHN), Prof. Rachel Harding, Department of Pharmacology and Toxicology, University of Toronto
Huntington’s disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by an expansion of ≥36 CAG trinucleotide repeats (encodes polyglutamine) in the huntingtin gene (Htt). HD is characterized by loss of neurons in the striatal and cortical areas of the brain, particularly medium spiny neuronal (MSNs) cells. However, the mechanism by which expression of mutant huntingtin leads to neuronal cell death remains the subject of intense research focus. To maintain normal synaptic communication, neurons heavily rely on mitochondrial-ATP production and are extremely sensitive to alterations in energy metabolism. Mitochondrial dysfunction is an early pathological mechanism thought to play an important role in selective neurodegeneration in HD. Mitochondrial dysfunction by mutant huntingtin is accompanied by release of mitochondrial RNAs (MT-RNAs) into the cytoplasm of the MSNs of human HD and mouse models of HD. This release of MT-RNAs was shown to trigger the innate immune signaling pathway within MSNs leading to cell death. MT-RNAs have been reported as cross-regulators of paraspeckle biogenesis by regulating long non-coding RNA (lncRNA) NEAT1 (nuclear paraspeckle assembly transcript 1) expression. LncRNA NEAT1 is a scaffold for paraspeckle formation, a nuclear sub-compartment that acts as a sensor of mitochondrial-stress and is required for mitochondrial homeostasis. NEAT1 levels have been previously reported to be altered in human HD tissues and HD mouse models.
In my PhD research, I have found that both wild-type and mutant huntingtin interact with specific RNAs. Specifically, RIP-seq experiments of immunoprecipitated huntingtin from normal and HD fibroblasts and isogenic neuronal progenitor cells, showed significant enrichment of lncRNA NEAT1. Gene ontology analysis of huntingtin RIP-seq data shows enriched transcripts are involved in various mitochondrial pathways such as ATP metabolic process, oxidative phosphorylation as well as in cytokine regulatory processes. Integrating these findings, we hypothesize that huntingtin-NEAT1 interactions are altered in HD cells contributing to a reduced ability to deal with mitochondrial stress, causing mitochondria-fragmentation, thus leading to MT-RNA release and innate immune activation. Aiming to understand the role of huntingtin-NEAT1 in managing mitochondrial stress, my research involves examining mitochondrial bioenergetics in wild-type and HD cell models after huntingtin and/or NEAT1 knockdown. My proposed studies will uncover a completely novel role for huntingtin in regulating paraspeckle biogenesis via interaction with lncRNA NEAT1 and provide a novel perspective on how mutant huntingtin may affect lncRNA metabolism and impact the cellular responses to mitochondrial stressors.
Human cerebral organoids to assess and treat severe epileptic/mitochondrial
Peter Carlan, Department of Neurology, Krembil Research Institute
Taufik Valiante, Department of Neurology, Krembil Research Institute
Approximately 1% of Canadians develop epilepsy in their lifetime with ~1/3rd being treatment resistant. This leads to chronic morbidity, greatly burdening the health care system, particularly in pediatric patients suffering from a severe epileptic encephalopathy. Epilepsy Canada reports that each year in Canada, an average of 15,500 people learn they have epilepsy; 75-85% before age 18. About one-quarter of patients with mitochondrial disease have epilepsy, most commonly present in pediatric patients with classical mitochondrial disease syndromes such as MELAS, MERFF, Leigh disease or POLG-related disorders. Overall, studies have shown that 40-60% of patients with mitochondrial disease develop seizures. Most cases of epilepsy with mitochondrial disorders are drug-resistant, associated with a very poor prognosis, often with a fatal outcome. Seizures, irrespective of their origin, represent an excessive acute energy demand in the brain. Accordingly, secondary mitochondrial dysfunction has been described in various epileptic disorders, including disorders that are mainly of non-mitochondrial origin making the role of mitochondrial dysfunction in epilepsy much more widespread than just originating from primary mitochondrial disorders.
The underlying biological hypotheses are: 1. Mitochondrial dysfunction is a frequent underlying cause of epilepsy, particularly in pediatric epileptic encephalopathies, and conversely, that recurrent seizures can cause mitochondrial dysfunction. 2. hCOs provide a model of severe epileptic encephalopathies useful for diagnosis, uncovering pathophysiology, and assessing various pharmacological and other treatment options. In the proposed study, as an engineer, I will focus on developing a robust and pathophysiological discovery platform using organoids to understand the impact of mitochondrial dysfunction on seizures and epilepsy.
Dana El Soufi El Sabbagh
Mitochondrial Enhancers for Neuropsychiatric Diseases
Ana Andreazza,Department of Pharmacology & Toxicology, U of T
Peter Carlan,Department of Neurology, Krembil Research Institute
Bipolar disorder (BD) is a major mood disorder characterized by cyclic periods of mania (high energy state) and depression (low energy state). There is a lack of progression in advancing novel therapeutics for BD in part due to the lack of biomarkers that could help to stratify patients through biological pathways that can guide targeted treatments, better diagnosis, management and improve disease trajectory. One of the leading hypothesis regarding BD pathology is due in part to the failure of mitochondrial function to support adequate neurotransmission and synaptic plasticity, thus affecting mood regulation, memory, and executive function. The mitochondrial dysfunction hypothesis is supported by studies showing higher frequency of mitochondrial (mt) DNA mutations; polymorphism in autosomal mitochondrial complex I genes; lactate levels; reactive oxygen species production; downregulation of NDUFS7, an essential mitochondrial complex I subunit. In addition, individuals with mitochondrial disease present psychiatric symptoms. Thus, it is critical to identify the potential role of mt dysfunction in mediating changes in neurotransmission and synaptic plasticity in patients with bipolar disorder. Cerebral organoids (COs) developed from patient-derived induced pluripotent stem cells (iPSCs) pose a hope to potentially model mitochondrial dysfunction and accelerate the development of tailored mitochondrial therapies. Therefore, the overall objective of this project is to identify novel mitochondrial enhancers that can restore brain mitochondrial health in bipolar disorder. To achieve this we will use well established CO models derived from iPSCs from patients with Bipolar Disorder (BD) (N=5) or patients with mitochondrial disease (N=5) in comparison to healthy controls (N=5) and treat with a matrix of mitochondrial enhancers such as but not limited to, ketones (beta-hydroxybutyrate; BHB) and complex antioxidant matrices (Euterpe oleracea, extract). We hypothesize that mitochondrial enhancers will ameliorate mitochondrial function in patients with bipolar disorder or mitochondrial disease. Ultimately, we aim to restore mitochondrial health and cellular homeostasis to a similar level observed in healthy controls.
The role of Rho in PKD-mediated mitochondrial remodeling
Andra Kupas, Professor, Department of Surgery and Biochemistry, Kennan Research Centre Unity Health
Rola Seepa , Professor, Department of Laboratory Medicine and Pathobiology, St. Michael’s Hospital, Unity Health
Autosomal Dominant Polycystic Kidney Disease (PKD) is the most common hereditary nephropathy, affecting 1 in ≈500 people (1). It is caused by loss-of-function mutations of one of two membrane proteins: Polycystin 1 (PC1, 85%) and Polycystin 2 (PC2, 10%) (2). PKD is characterrized by excessive cyst formation and fibrosis, leading to end-stage renal disease (3). While the mechanisms underlying PKD-associated cystogenesis has been gradually unravelled, very little is known about the mechanism of fibrogenesis. Notably, one of the hallmarks of PKD at the cellular level is robust mitochondrial remodeling (fragmentation). This process is associated with profound metabolic changes (e.g. impaired OXPHOS, enhanced ROS production) (4). Importantly, the mechanism governing PKD-associated mitochondrial fragmentation is essentially unknown. Interestingly, similar mitochondrial shape changes and functional alterations were observed also in other forms of chronic kidney disease leading to fibrosis (5). This scenario then prompts our two central aims: 1) Define the molecular mechanisms underlying PKD-associated mitochondrial fragmentation; 2) Assess whether mitochondrial remodeling contributes to the pathogenesis of fibrosis in the context of PK
Investigating the effects of phosphorylation of CHIP on alpha synuclein mediated mitophagy
Suniel Kalia, Department of Laboratory Medicine and Pathobiology, UHN
Joel Watts, Department of Biochemistry, University of Toronto
Parkinson’s disease (PD) is a neurodegenerative disease affecting approximately 3% of the population over the age of sixty-five and is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pas compacta (SNpc). There is no cure for PD and the best treatment options for patients only provide symptomatic relief. Thus, understanding the underlying pathways of PD is crucial for determining the etiology and generating a cure for this disease. While PD is largely a sporadic disorder, several genes have been linked to heritable forms, revealing underlying molecular pathways that may be implicated in this disease. For example, mutations in the alpha synuclein (αsyn) encoding SNCA gene, such as A53T, A30P, or E46K missense mutations are linked to autosomal dominant forms of familial PD3. Interestingly, mitochondria dysfunction has been highly implicated in the pathogenesis of PD5 , and αsyn has been demonstrated to have detrimental effects on mitochondria function. Using the dual fluorophore reporter FIS1-mcherry-EGP (‘mito-QC’)9 I have demonstrated increased mitochondria autophagy (mitophagy) in primary cortical neurons overexpressing A53T, human induced pluripotent stem cell-derived dopaminergic neurons (hiPSC-DA) harboring the A53T mutation, and in an in vivo rat model of A53T. Evidently, mutant αsyn has downstream consequences on mitochondria health and thus determining its upstream regulator could prove vital in decreasing a syn damage to mitochondria. The co-chaperone carboxyl terminus of heat shock protein 70- interacting protein (CHIP) is a promising candidate for regulating levels of αsyn in the cell. CHIP is an E3 ubiquitin ligase and molecular cochaperone and previous work by our lab has shown that CHIP ubiquitinates toxic αsyn oligomers, targeting them for degradation.
This suggests that CHIP plays an important role in regulating αsyn. However, despite the importance of CHIP in the pathogenesis of PD, its regulation remains poorly understood. Using mass spectrometry, our lab, in collaboration with the Schmitt-Ulms lab, has demonstrated increase in serine 19-phosphorylated CHIP (pCHIP-S19) upon treatment of the mitochondria toxin carbonyl cyanide m-chlorophenyl hydrazine. I have identified a kinase that phosphorylates CHIP at S19, and my preliminary results suggest that pCHIP-S19 may enhance the ability of CHIP to degrade αsyn (Data not shown). Thus, I am interested in exploring the potential functional implications of pCHIP-S19 on αsyn regulation and associated mitochondria dysfunctions.
Mitochondrial Dysfunction in Mild Vascular Cognitive Impairment
Dr. Krista Lanctôt, Professor, Department of Pharmacology & Toxicology and Psychiatry, University of Toronto
Cognitive decline in older adults has been linked to a higher risk of mortality, lower quality of life, and decline in activities of daily living17. Similarly, it has been reported that the rate of mVCI progression to dementia and their mortality rates are high4 . This study will explore an association between mitochondrial dysfunction and cognitive decline and help identify a novel biomarker of vascular dementia and mVCI. The findings may provide further understanding of the disease etiology, which may provide novel therapeutic targets for preventing cognitive decline in individuals with mVCI, a disorder with no cure.
Surveying the TAZ mutational landscape in yeast and human cell
Jason Moffat, Department of Molecular Genetics University of Toronto
Charlie Boone, Department of Molecular Genetics, University of Toronto
The genotype-to-phenotype relationship in health and disease is complex, influenced by environmental and genetic factors. Unmasking the non-trivial pairwise genetic interactions on a genome-wide scale remains an active area of investigation in many prominent disease models. The diverse spectrum of phenotypes observed in Barth Syndrome (BTHS), caused by mutations in the gene TAZ is consistent with such complex genotype-to-phenotype interplay, however, systematic efforts to understand these interactions remain lacking. Furthermore, numerous mutations in the TAZ gene have been documented in BTHS patients, including frameshift and point mutations, as well as mutations that disrupt alternative splicing of TAZ.
This diverse pattern of TAZ mutations suggests that several independent mechanisms contribute to a loss or altered function of Tafazzin, the protein product of TAZ, which may account for the broad phenotypic variance observed in patients. Despite the documented mutations, little is known about the genetic and protein interactions of TAZ/Tafazzin, or the genetic architecture of TAZ and which mutations are functionally consequential. Moreover, it remains unclear whether Tafazzin moonlights in alternative processes unrelated to its highly conserved acyltransferase that may contribute to the pathology of BTHS. Using deep mutational scanning approaches, we propose to further characterize the TAZ gene to understand other functional roles of Tafazzin in yeast and human cells.
Developing Metabolic Therapies for Heart Disease by Harnessing the Regenerative Potential of the Pediatric Heart
Dr. Jason Maynes, Associate Professor, Departments of Anesthesiology and Pain Medicine and Biochemistry, Faculty of Medicine University of Toronto
Dr. Paul Santerre , Professor, Department of Chemical Engineering & Applied Chemistry, University of Toronto
Heart disease is the leading cause of morbidity and mortality worldwide, imparting significant medical and socioeconomic costs. Owing to its continuous mechanical work, the heart requires large amounts of ATP to function optimally (between 20-70 times its own weight daily)1,2. Healthy and efficient mitochondria are therefore required for maintaining homeostatic energy demands. Adverse changes in mitochondrial structure and function are prominent features of cardiomyocyte dysfunction in the failing heart3 . Preventing or mitigating these adverse changes has the potential to improve the efficiency of cardiomyocyte metabolism and consequently improve organ function, representing a novel therapy for heart failure. The pediatric human heart has a higher inherent capacity for self-repair compared to the adult heart. Consistent with this observation, the secreted (paracrine) biomolecules produced by cardiac progenitor cells procured from pediatric hearts can more potently induce repair to damaged tissue4 . Collectively known as the cell’s secretome, these biomolecules can include diverse constituents including exosomes, proteins, RNA, and metabolites, reflecting their cell of origin and playing an important role in inter-cellular signalling and crosstalk5 . The effect of these secretomes on cardiomyocyte metabolism and mitochondrial health has not been thoroughly studied. I hypothesize that administration of secretome derived from pediatric cardiac progenitor (stem) cells can preserve and possibly enhance cardiomyocyte function and mitochondrial oxidative phosphorylation capacity in both in vivo and in vitro models of heart disease.
Mitochondrial transplantation as a rescue strategy for the treatment of injured
lungs allocated for transplantation
Marcelo Cypel, Department of Surgery, Toronto General Hospital
Ana Andreazza, Department of Pharmacology & Toxicology, U of T
Some of the challenges faced by the field of lung transplantation with the highest potential impact on outcomes are improving organ preservation in a way that allows viability to be protracted, providing time for additional innovative therapies to be applied, and recovering injured lungs that would otherwise not be acceptable for transplantation, which is both a consequence of improved preservation and an additional hurdle in itself. Current standard practice of cold static preservation (CSP) of donor lungs with ice cooling at approximately 4ºC limits storage of the organs for approximately 6-8 hours. The Toronto’s Ex-Vivo Lung Perfusion (EVLP) technique, developed in 2008 by our lab, is an innovative platform that simulates an in vivo environment prior to transplantation. In our most recent publication, we were able to demonstrate for the first time the feasibility of 3-day lung preservation by adding two four-hour cycles of EVLP to a 10ºC CSP, achieving exceptional functional results. In common to our previous findings in which extended CSP at 10 degrees showed benefits over the current standard of 4ºC, this successful approach seems to be correlated with improved mitochondrial health.
Albeit remarkable, these encouraging results observed in healthy lungs preserved for extended periods may not always reflect the reality of many of the organs clinically available for transplantation, which frequently present some degree of injury and inflammation. In a paper from our lab recently submitted to the Journal of Heart and Lung Transplantation, we show for the first time that 10°C can also be a superior storage temperature in the context of aspiration-induced lung injury. Taken together, the data notably suggested that protecting the mitochondria could be an effective therapeutic target for future investigations. Since 2009, the concept of mitochondrial transplantation (MT) emerged as a potentially effective means for reducing ischemia-reperfusion injury (IRI) and extending organ preservation in heart, brain, kidney, and lung. Furthermore, these findings have been already translated to a clinical trial
Metabolic Regulation of Neutrophil Biology in a Murine Model of Severe
Robert Bandsma, Department of Pediatrics, Hospital for Sick Children
Michael Glogauer, Professor, Faculty of Dentistry, University of Toronto
Severe undernutrition, referred to as malnutrition in this proposal, is associated with a high risk of morbidity and mortality in children under five years of age, markedly in resource-poor countries. Poor host responses and the occurrence of repeated bacterial infections, allows these infections to progress more easily into severe clinical septic phenotypes that underlie these adverse outcomes. The underlying immune and metabolic dysregulations are not corrected by the standardized WHO guidelines1 . Therefore, relapse is common, and hospital fatality rate remains high1 . While malnutrition is known to influence innate immunity, the first line of defense that initially responds to pathogenic microbes, a greater mechanistic understanding is required of these processes to address this global issue. Neutrophils, found to be increased in the circulation of children with malnutrition, are first responder cells of the innate immune system that influence and regulate the inflammatory response for pathogen clearance through their large repertoire of effector functions (chemotaxis, phagocytosis, ROS formation, degranulation, neutrophil extracellular traps (NETs) formation, and production of cytokines and other inflammatory mediators)
As result, I aim to (1) Define, in mice, effects of severe malnutrition on differentiation and immune functions of neutrophils actively responding to infection in the bone marrow and tissues, respectively. (2) Delineate, in mice, the malnutrition-induced metabolic disturbances that impair neutrophil development and functions.
Identification of mitochondrial nuclear export cargo and modulation by the
XPO1 inhibitor selinexor in diffuse large B cell lymphoma
John Kuruvilla, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre
Armand Keating, IBBME, University of Toronto
Exportin 1 (XPO1), a nuclear export protein, is overexpressed in almost all patients with solid and hematological cancers . In normal cells, XPO1 mediates the export of RNA, ribosomal subunits, and various proteins from the nucleus to the cytoplasm. However, cancer cells hijack the activity of XPO1 to mislocalize proteins for their benefit. For example, XPO1 can mediate the cytoplasmic mislocalization of DNA damage response proteins such as p53, resulting in cancer cell growth and chemotherapy resistance. Selinexor is a novel anti-cancer agent that inhibits the nuclear export of these proteins via the obstruction of XPO1. Although selinexor has been approved for use in relapsed/refractory diffuse large B cell lymphoma (DLBCL) , knowledge gaps in understanding precisely what XPO1 exports in DLBCL and how selinexor impacts this prevents the drug from being used optimally in the clinic. Of increasing importance is the role of mitochondrial metabolism, as evidence in recent years has indicated that cancer cells commandeer oxidative phosphorylation to increase the availability of substrates for growth and invasion.
However, the mechanisms by which nuclear export influences mitochondrial function are lacking. Our preliminary data indicates that selinexor is able to decrease oxidative metabolism and ATP production in DLBCL while leaving glycolysis unaffected. This indicates that XPO1 mediated nuclear export plays a role in mitochondrial function. By identifying what proteins are exported by XPO1 in DLBCL and how they influence the mitochondria, a more in-depth understanding of the XPO1-mitochondrial axis will be delineated. This will allow us to better understand the role of nuclear export in regulating mitochondrial function, which may be pertinent not only to cancer, but other human diseases as well. In addition, this will enable us to further understand selinexor’s mecha.
JOIN THE MITO INNOVATION SCHOLAR COMMUNITY
MITO2i is dedicated to advancing mitochondrial research and fostering innovation. Our innovation grants, fellowships, and scholarships are instrumental in promoting interdisciplinary collaboration, leading to transformative breakthroughs in the field of mitochondrial medicine.
The projects funded by MITO2i showcase the diverse array of fields and disciplines exploring the intricacies of mitochondrial function and dysfunction, extending beyond mitochondrial diseases to encompass various chronic conditions. These initiatives are poised to generate novel insights and ideas across a broad spectrum of research areas, significantly expanding the horizons of mitochondrial medicine and research.
If you have a project that aligns with MITO2i’s vision, feel free to contact us, become a member, and/or follow our social media to receive announcements on upcoming opportunities! A limited number of MITO2i graduate student scholarships are awarded each year – applications will open in the spring.
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.