Mitochondrial Metabolic Regulation of GABAergic Interneurons

Project Summary/Abstract Primary Mitochondrial Diseases (PMDs) result from intrinsic dysfunction of mitochondria and have a prevalence of 1 in 5,000. Although over half experience neurologic symptoms, PMDs are heterogeneous both genetically and phenotypically. Given the disease heterogeneity, metabolic pathways common to multiple forms of PMD are appealing therapeutic targets. However, the full extent of mitochondrial metabolism in neurons is incompletely understood as in addition to generating energy in the form of ATP through the electron transport chain (ETC), mitochondria also generate metabolites through the TCA cycle and reactive oxidation species, any of which may contribute to neuronal function. The foundation of this proposal is based on preliminary studies indicating that the mitochondrial TCA cycle plays a critical role in GABAergic inhibitory interneurons which are essential for regulating excitatory neuronal circuits. The focus of the proposal is to test whether the ETC is required for inhibitory interneuron survival or GABA metabolism. The two aims will: (1) use an in vitro iPSC-derived inhibitory interneuron system to evaluate acute manipulation of mitochondria; and (2) use mice lacking mitochondrial function in hippocampal GABAergic interneurons to establish the effects of chronic mitochondrial impairment. The scientific purpose of this proposal is to begin defining the effects of mitochondrial metabolism in GABAergic hippocampal neurons, with the vision of expanding the tools and measurements in GABAergic neurons including those outside the hippocampus, and eventually translate findings by therapeutically targeting metabolism to promote neuronal health in mitochondrial disease. The proposal is a five-year physician-scientist development program for the candidate who is an Assistant Professor of Pediatrics at Northwestern University, with 75% protected time for research, independent laboratory space and start-up funding. In addition, his clinical time at Lurie Children’s is dedicated to managing children with mitochondrial disease in both the outpatient and inpatient critical care setting. He is committed to a career in translational mitochondrial metabolism research focused on neurologic symptoms and is strongly supported by his Department of Pediatrics, Section of Child Neurology and his mentorship team. The candidate will build on his prior experience in neuroscience by learning advanced techniques in mitochondrial metabolism research under the guidance of his primary mentor, Dr. Navdeep Chandel. Additionally, his co- Mentor, Dr. Mustafa Sahin at Boston Children’s and Harvard, will provide project- and career-level guidance as an experienced translational researcher and child neurologist. Together, the proposed experiments, collaborations with experts, advice from consultants and formal didactics will provide the skills and experience for his transition to independence as a physician-scientist with unique expertise studying mitochondrial metabolism in neurons, with the long term goal of translating the findings into treatments for PMD.