George Karpati Lecture - Mitochondrial Medicine: from Mechanisms to Treatments
The Annual George Karpati Lecture commemorates a world-renowned neurologist and clinician-scientist who spent his extraordinary career at The Neuro. George was respected for his great contributions to the diagnosis and treatment of neuromuscular diseases and for his research into the causes and possible cures for neuromuscular diseases, and especially muscular dystrophy. His colleagues at The Neuro organize this lecture on recent developments in neuromuscular disease research and treatment, as a tribute to a friend, mentor, and scientific leader.
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Speaker: Rita Horvath, MD, PhD
Department of Clinical Neurosciences, University of Cambridge
Abstract:
Mitochondrial diseases are clinically and genetically very heterogeneous, and can be caused by mutations in the mitochondrial DNA (mtDNA) or in over 400 nuclear genes. They can affect multiple neurological systems, and also often involve other non-neurological organs and tissues. Specific clinical syndromes have been associated with some mitochondrial diseases, but there is considerable phenotypic overlap with other neuromuscular and neurometabolic diseases. Therefore first-line exome and whole genome sequencing have become a cost-effective way of reaching a molecular diagnosis promptly in mitochondrial disease. Despite the significantly improved diagnostic yield, there are still no effective treatments for most patients with mitochondrial disease.
Mitochondria play a central role in the homeostasis of cells, but mitochondrial insults preferentially affect some cell-types and not others. The reasons for this are not clear. The aim of our research is to define principal mechanisms underpinning cell-type-specific mitochondrial vulnerability in different organs and cell types. We use iPSC-derived neuronal models of mitochondrial disease including brain organoids to better understand this vulnerability in neurons. To study the effect of mitochondrial dysfunction in vivo, we applied CRISPR/Cas9 mutagenesis in zebrafish. The data obtained in neuronal cells and in zebrafish highlight some relevant molecular pathways which we utilise to develop treatments for mitochondrial disease.
