The goal of this application is to identify phospholipid biomarkers of environmentally-induced (rotenone- induced) mitochondrial dysfunction associated with Parkinson's disease PD. We demonstrated that a mitochondria specific phospholipid, cardiolipin (CL), undergoes selective oxidation catalyzed by cytochrome c (cyt c) early during neuronal apoptosis. Our central hypothesis is that exposure to a pesticide, rotenone, causes time- and dose-dependent selective oxidation of CL and accumulation of its oxidized molecular species associated with mitochondrial dysfunction through enzymatic cyt c catalyzed reactions triggered early in apoptosis. The unique profile of CL molecular species represents a new type of biomarkers of rotenone-induced mitochondrial dysfunction associated with PD. Using oxidative lipidomics approach we will first identify specific patterns of CL oxidized molecular species induced in rat primary cortical and midbrain neurons as well as neuroblastoma SH-SY5Y by rotenone. Further, we will reveal the specific profiles of oxidized CL species in dopaminergic and cortical neurons using rat rotenone- infusion model of PD. Finally we will establish the presence of the rotenone-specific CL oxidation patterns in human peripheral blood lymphocytes exposed to rotenone and compare them with those detected in rotenone-infusion rat model. The following Specific Aims were developed to test the hypothesis:
Specific Aim 1 will utilize oxidative lipidomics to identify and characterize molecular species of CL as well as unique stereo-specific oxygenated products of CL in primary rat cortical neurons and midbrain neurons as well as in SH-SY5Y cells upon exposure to rotenone.
Specific Aim 2 will establish the mechanisms and pathways through which interactions of cyt c with CL are involved in CL oxidation in primary rat cortical and midbrain neurons as well as SH-SY5Y cells exposed to rotenone.
Specific Aim 3 will determine the extent to which molecular species of rotenone-induced peroxidized CL detected and identified in neurons in vitro accumulate in mitochondria of cortical and midbrain neurons in vivo after infusion of rotenone to rats.
Specific Aim 4 will reveal rotenone-specific CL peroxidation patterns in human peripheral blood lymphocytes as biomarkers of mitochondrial dysfunction associated with PD.

Public Health Relevance

The goal of this application is to identify biomarkers of environmentally (rotenone)-induced mitochondrial dysfunction associated with Parkinson's Disease. This will be achieved by a novel oxidative lipidomics approach. Rotenone-specific peroxidation patterns of mitochondrial cardiolipins will be identified in rat cortical and midbrain neurons in vitro and in vivo and revealed in human peripheral blood lymphocytes.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZES1-LWJ-J (MI))
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Shaughnessy, Daniel
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University of Pittsburgh
Public Health & Prev Medicine
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Hassannia, Behrouz; Wiernicki, Bartosz; Ingold, Irina et al. (2018) Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Invest 128:3341-3355
Tyurina, Yulia Y; Shrivastava, Indira; Tyurin, Vladimir A et al. (2018) ""Only a Life Lived for Others Is Worth Living"": Redox Signaling by Oxygenated Phospholipids in Cell Fate Decisions. Antioxid Redox Signal 29:1333-1358
Wenzel, Sally E; Tyurina, Yulia Y; Zhao, Jinming et al. (2017) PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell 171:628-641.e26
Doll, Sebastian; Proneth, Bettina; Tyurina, Yulia Y et al. (2017) ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 13:91-98
Kooijman, E E; Swim, L A; Graber, Z T et al. (2017) Magic angle spinning 31P NMR spectroscopy reveals two essentially identical ionization states for the cardiolipin phosphates in phospholipid liposomes. Biochim Biophys Acta Biomembr 1859:61-68
Tyurina, Yulia Y; Lou, Wenjia; Qu, Feng et al. (2017) Lipidomics Characterization of Biosynthetic and Remodeling Pathways of Cardiolipins in Genetically and Nutritionally Manipulated Yeast Cells. ACS Chem Biol 12:265-281
Kagan, Valerian E; Mao, Gaowei; Qu, Feng et al. (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13:81-90
Kagan, Valerian E; Bay?r, Hülya; Tyurina, Yulia Y et al. (2017) Elimination of the unnecessary: Intra- and extracellular signaling by anionic phospholipids. Biochem Biophys Res Commun 482:482-490
Vlasova, Irina I; Kapralov, Alexandr A; Michael, Zachary P et al. (2016) Enzymatic oxidative biodegradation of nanoparticles: Mechanisms, significance and applications. Toxicol Appl Pharmacol 299:58-69
Banerjee, Kalpita; Munshi, Soumyabrata; Xu, Hui et al. (2016) Mild mitochondrial metabolic deficits by ?-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: Potential role in the pathobiology of Alzheimer's disease. Neurochem Int 96:32-45

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