Trevor Young, Professor, Department of Psychiatry and Pharmacology, University of Toronto

The overall goal of this study is to use linked population health databases to characterize the epidemiology of mitochondrial disease and the co-occurrence with mental health conditions in Ontario. Our specific objectives are to examine: (1) the health care burden and costs associated with mitochondrial disease in a population- based cohort in Ontario: (2) the association between mood disorders and other mental health conditions in patients with mitochondrial disease: and(3) the joint impact of mental health conditions on the health care use. costs and mortality.

This study represents the first to establish a methodological approach to measure mitochondrial disease from population data across Canada. For the first time in Canada. we will contribute key epidemiological evidence to inform health and health care for those living with mitochondrial conditions. and further support hypotheses and research on the relationship between mitochondrial disease and mental health This project will build the fundamental methodology that can be replicated in other Canadian provinces, and enable future international research. including comparisons of mitochondrial disease populations and further study of health care utilization and costs

Katarzyna Jerzak, Medical Oncologist, Odette Cancer Centre, Sunnybrook Hospital

David Andrews, Senior Scientist and Director, Biological Sciences, Sunnybrook Research Institute

Breast cancer (BC) is the number one cancer killer of women Improving survival and quality of life for patients with BC is limited by our ability to effectively personalize systemic therapies. reducing the risk of treatment resistance and disease recurrence. while minimizing the risks of toxicity associated with ineffective chemotherapeutic agents. Selection of an appropriate therapy for patients with locally advanced breast cancer (LABC). which typically involves treatment with chemotherapy prior to surgery. involves significant trial-and-error. Most patients receive a standard cocktail of drugs. but only about one-third have a positive and complete response. We need to gather more information about how each patient’s tumour cells can be killed: in effect. Pa personalizing treatment

Here we propose to identify genes in mitochondria of cancer cells that may contribute to their growth. survival and ability to develop resistance to chemotherapy. We now know that cancer cells can use nutrients differently from normal cells, which raises the possibility of new strategies to kill them We call these 4 ‘mitochondrial metabolism vulnerabilities’ Our novel approach will be to silence mitochondrial genes in LABC cells taken directly from patients using state-of-the-art genetic and imaging tools to identify tumour-specific vulnerabilities. These vulnerabilities can then be targeted alone or in conjunction with lower doses of established therapies to kill tumours more effectively reducing side effects. An exciting outcome of this work is the development of patient-specific therapies not based on trial-and-error. but a personalized approach based on the patient’s own tumour’s demonstrated drug sensitivities.

Evdokia Anagnostou, Child Neurologist, Holland Bloorview Research Institute

Stephen Scherer, Senior Scientist, Genetics and Genome Biology, Hospital for Sick Children

Jessica Brian, Psychologist and Clinician-Investigator, Holland Bloorview, Kids Rehabilitation Hospital

Autism spectrum disorder (ASD) is a severe early onset neurodevelopmental disorder demonstrating defects in social communication/interactions and repetitive patterns of behaviour. It occurs in – 1 % of the population and in 10-20% of mitochondrial disorders. with intellectual disability (IDiin – 50 % of cases. attention deficit hyperactivity disorder in 25-50 % and frequent psychiatric disorders. High-impact genetic mutations in key neurodevelopmental genes account for – 20 % of ASD. Metabolic factors are also described in up to 10-20% of children which include abnormalities in the mitochondria, the energy-generating batteries of the cell. and in the camitine (Cn)-dependent system L-Cn is often used to treat mitochondrial disorders and is a key. safe vitamin that is important in generating energy for the brain. protecting it from toxic free radicals and helping neurotransmission The brain has 3 Cn transporters and dysfunction of one is associated with ADHD and 1D 2 with significant improvement with Cn therapy Certain children with ASD have had a positive response to Cn.particularly those with defects in the Cn pathway.

We plan to identify genetic risk variants in the Cn transporter and Cn biosynthesis gene families. as well as clinical risk factors leading to Cn deficiency in a group of children with ASD. Our approach will select Cn- relevant children for potential future clinical trials to test who may have a beneficial response to Cn leading to improved social communication. attention, and learning The earlier the identification of children at risk, the greater the effect on brain development and quality of life.

Shamima Rahman, Professor, UCL Great Osmond Street Institute of Child Health

Perrault syndrome is an autosomal recessive rare mitochondrial disorder characterized by hearing loss in both males and females with females also experiencing ovarian failure. However. the disease is clinically heterogenous and affected patients exhibit additional neurological symptoms including spasticity, ataxia, and neuropathy. Mutations in six different genes. five of which encode mitochondrially-targeted proteins. have so far been linked to Perrault syndrome. One of these genes is CLPP. which encodes the mitochondrial ClpP protease. Human ClpP is a nuclear-encoded serine protease that is translocated to the mitochondria viaan N- terminal targeting sequence. In the mitochondria. ClpP assembles into a tetradecameric cylinder hat associates with an ATPase cap The resulting ATPase-protease complex is involved in the degradation of several critical mitochondrial matrix and inner membrane proteins.

Currently, it is not known how CLPP mutations result in Perrault syndrome and there are no disease-modifying curative therapies. Current management is symptomatic only and includes cochlear implantation and ovarian hormone replacement. Effective therapies are urgently needed. especially to address the neurodegenerative aspects of this disease. In this work, we propose to investigate and characterize model and patient-derived cell lines carrying CLPP mutations to determine the molecular pathogenic basis of this mitochondrial disease. Furthermore. the effect of compounds targeting ClpP on cell biology and physiology will also be studied. This project is a close collaboration between two groups with excellent expertise in ClpP biochemistry, biology, and treating patients with Perrault syndrome. The project has clear translational potential and is expected to advance the field of mitochondrial medicine.

Iris Asllani, MR Physicist and Research Associate Professor, Brighton and Sussex Medical School

Robert Pitceathly, MRC Clinical Scientist, UCL Institute of Neurology and National Hospital of Neurology and Neurosurgery

Involvement of the brain in mitochondrial disease is common and as a consequence. neurological manifestations. including also neuropsychiatric symptoms such as mood alterations. are very frequent. There 4 has been no systematic study of these clinical aspects which are often missed and greatly disabling. Therefore, the neuropsychiatric aspects of mitochondrial disease remains very poorly defined. Information on how to do accurate and precise assessment of neuropsychiatric symptoms in mitochondrial disease is largely missing. which limits the ability of developing treatment trials targeting these symptoms. Furthermore. there is a critical need of defining biomarkers for brain involvement in mitochondrial disease, to learn how to best measure the effects of new therapeutics, in order to promote discovery of novel effective medications.

Our study will integrate precise neuropsychiatric assessment. based on use of validated diagnostic instruments, cognitive testing. and tracking of mood fluctuations, with state-of-the-art neuroimaging techniques to assess brain metabolism and micro-structure, in adult patients with mitochondrial disease. The findings from this research will improve the evaluation of therapeutic interventions and signposting to appropriate services. and will enable precise assessment in future trials of novel therapeutics improving mitochondrial function in the brain. Our project will therefore directly benefit patients with mitochondrial disease by contributing to better management of these disabling symptoms. and to the discovery of new effective treatments. The inter-disciplinary nature of the proposed research, integrating aspects of physical. brain, and mental illness, will contribute to tackle the stigma of mental health that patients with pathologies of the brain still regularly experience.

Marcelo Cypel, Surgical director, Ajmera Transplant Centre, University Health Network

Milica Radisic, Professor, University of Toronto

Ori Rotstein, Vice-President Research & Innovation, Unity Health

Frank Gu, Professor, University of Toronto

Sowmya Viswanathan, Scientist, University Health Network

David Bodenstein (Andreazza Lab), Gabriel Siebiger (Cypel Lab), Yimu Zhao (Radisic Lab), Aaron Clasky (Gu Lab), Avinash Mukkala (Rotstein Lab)

This project aims to advance mitochondrial transplantation as a regenerative medicine tool. Our approach integrates innovative techniques, including developing a robust mitochondrial delivery system and leveraging organ-on-a-chip technology. Central to our method is the precise delivery of functionally intact mitochondria in combination with the strategic matching of mitochondrial haplogroups (mitochondrial DNA variations), which together amplify the efficacy of organ regeneration and disease treatment.

By establishing pre-clinical and safety data, we aim to advance larger clinical trials targeting chronic diseases, particularly mitochondrial rare diseases. Through this innovative approach, we plan to establish mitochondrial transplantation as a novel treatment and revolutionize the landscape of medicine.