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)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-LWJ-J (MI))
Program Officer
Shaughnessy, Daniel
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Public Health & Prev Medicine
Schools of Public Health
United States
Zip Code
Mohammadyani, Dariush; Tyurin, Vladimir A; O'Brien, Matthew et al. (2014) Molecular speciation and dynamics of oxidized triacylglycerols in lipid droplets: Mass spectrometry and coarse-grained simulations. Free Radic Biol Med 76:53-60
Kagan, Valerian E; Chu, Charleen T; Tyurina, Yulia Y et al. (2014) Cardiolipin asymmetry, oxidation and signaling. Chem Phys Lipids 179:64-9
Amoscato, A A; Sparvero, L J; He, R R et al. (2014) Imaging mass spectrometry of diversified cardiolipin molecular species in the brain. Anal Chem 86:6587-95
Jiang, Jianfei; Bakan, Ahmet; Kapralov, Alexandr A et al. (2014) Designing inhibitors of cytochrome c/cardiolipin peroxidase complexes: mitochondria-targeted imidazole-substituted fatty acids. Free Radic Biol Med 71:221-30
Stoyanovsky, D A; Sparvero, L J; Amoscato, A A et al. (2014) Improved spatial resolution of matrix-assisted laser desorption/ionization imaging of lipids in the brain by alkylated derivatives of 2,5-dihydroxybenzoic acid. Rapid Commun Mass Spectrom 28:403-12
Tyurina, Yulia Y; Domingues, Rosario M; Tyurin, Vladimir A et al. (2014) Characterization of cardiolipins and their oxidation products by LC-MS analysis. Chem Phys Lipids 179:3-10
Chu, Charleen T; Bayýýr, Hulya; Kagan, Valerian E (2014) LC3 binds externalized cardiolipin on injured mitochondria to signal mitophagy in neurons: implications for Parkinson disease. Autophagy 10:376-8
Tyurina, Yulia Y; Poloyac, Samuel M; Tyurin, Vladimir A et al. (2014) A mitochondrial pathway for biosynthesis of lipid mediators. Nat Chem 6:542-52
Tyurin, V A; Balasubramanian, K; Winnica, D et al. (2014) Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic 'eat-me' signals: cleavage and inhibition of phagocytosis by Lp-PLA2. Cell Death Differ 21:825-35
Tyurina, Yulia Y; Winnica, Daniel E; Kapralova, Valentina I et al. (2013) LC/MS characterization of rotenone induced cardiolipin oxidation in human lymphocytes: implications for mitochondrial dysfunction associated with Parkinson's disease. Mol Nutr Food Res 57:1410-22

Showing the most recent 10 out of 13 publications