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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AG030821-01
Application #
7333576
Study Section
Special Emphasis Panel (ZDA1-MXH-H (09))
Program Officer
Wise, Bradley C
Project Start
2007-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$58,081
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Chu, Charleen T; Bay?r, Hülya; Kagan, Valerian E (2014) LC3 binds externalized cardiolipin on injured mitochondria to signal mitophagy in neurons: implications for Parkinson disease. Autophagy 10:376-8
Dagda, Ruben K; Pien, Irene; Wang, Ruth et al. (2014) Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through protein kinase A. J Neurochem 128:864-77
Chu, Charleen T; Ji, Jing; Dagda, Ruben K et al. (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol 15:1197-1205
Dagda, R K; Gusdon, A M; Pien, I et al. (2011) Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease. Cell Death Differ 18:1914-23
Dagda, Ruben K; Sultana, Tamanna; Lyons-Weiler, James (2010) Evaluation of the Consensus of Four Peptide Identification Algorithms for Tandem Mass Spectrometry Based Proteomics. J Proteomics Bioinform 3:39-47
Dagda, Ruben K; Cherra 3rd, Salvatore J; Kulich, Scott M et al. (2009) Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 284:13843-55
Chu, Charleen T; Plowey, Edward D; Dagda, Ruben K et al. (2009) Autophagy in neurite injury and neurodegeneration: in vitro and in vivo models. Methods Enzymol 453:217-49
Dagda, Ruben K; Chu, Charleen T (2009) Mitochondrial quality control: insights on how Parkinson's disease related genes PINK1, parkin, and Omi/HtrA2 interact to maintain mitochondrial homeostasis. J Bioenerg Biomembr 41:473-9
Cherra 3rd, Salvatore J; Dagda, Ruben K; Tandon, Anurag et al. (2009) Mitochondrial autophagy as a compensatory response to PINK1 deficiency. Autophagy 5:1213-4
Dagda, Ruben K; Zhu, Jianhui; Chu, Charleen T (2009) Mitochondrial kinases in Parkinson's disease: converging insights from neurotoxin and genetic models. Mitochondrion 9:289-98

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