Dysregulated autophagy has been implicated in several human neurodegenerative diseases and their models. Macroautophagy is a regulated process for engulfment of cytoplasmic constituents into organelles termed autophagosomes, which deliver the cargo to lysosomes for degradation. Autophagic sequestration requires conjugation of components of the autophagy machinery to the pre-autophagosome membrane.Basal autophagy is critical for maintaining mitochondria) homeostasis in neurons, and either impaired or excessive mitochondria! turnover may contribute to neurodegeneration. However, mechanisms that regulate selective targeting of damaged organelles such as mitochondria are unknown. Our recent study indicates that alternative lipid signals are involved in signaling mitochondria! Autophagy during parkinsonian injury, and these signals are distinct from the commonly studied lipid signals that regulate nonselective starvation-induced autophagy. We hypothesize that oxidation and exposure of the mitochondria! inner membrane phospholipid cardlolipln (CL) triggers mitophagy through interactions with the autophagy machinery. Interdisciplinary approaches including mass spectrometry, high performance thin layer chromatography, lipid coated nanoparticles, live cell imaging, and mutational analysis will be employed to test this hypothesis through two specific aims that focus on the role of CL in triggering mitophagy and the mechanism of interaction with the autophagy machinery. The applicant is a postdoctoral fellow with experience in molecular neuropharmacology. To conduct the proposed studies, he will train under the multidisciplinary mentorship of experts in autophagic cell biology and Parkinson's disease mechanisms, oxidative lipidomics and nanotechnology, computational biology and specialized biologic imaging techniques. Regular meetings involving the applicant, his interdisciplinary mentoring team, and external advisors will be held to ensure effective integration of molecular cell biologic, biochemical and neurodegenerative considerations. The two-year research training plan will enable the applicant to derive career developmental skills to become an independent investigator in neurodegeneration research. Lay Summary. In addition to powering cellular energy needs, mitochondria actively regulate neuronal survival/death decisions. Mitochondria! alterations are implicated in neurodegenerative and ? psychiatric diseases and in aging. As autophagy is a key factor in mitochondria! quality control, scientific innovations from the proposed research can benefit the larger community by unveiling therapeutically relevant mechanisms in Parkinson's and other age-related neurodegenerative processes. ? ? ?
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