Protein Modification by Endogenously Generated Lipid Electrophiles: Mitochondria as the Source and Target

William N. Beavers; Kristie L. Rose; James J. Galligan; Michelle M. Mitchener; Carol A. Rouzer; Keri A. Tallman; Connor R. Lamberson; Xiaojing Wang; Salisha Hill; Pavlina T. Ivanova; H. Alex Brown; Bing Zhang; Ned A. Porter; Lawrence J. Marnett

doi:10.1021/acschembio.7b00480

Protein Modification by Endogenously Generated Lipid Electrophiles: Mitochondria as the Source and Target

William N. Beavers, Kristie L. Rose, James J. Galligan, Michelle M. Mitchener, Carol A. Rouzer, Keri A. Tallman, Connor R. Lamberson, Xiaojing Wang, Salisha Hill, Pavlina T. Ivanova, H. Alex Brown, Bing Zhang, Ned A. Porter, Lawrence J. Marnett

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

Determining the impact of lipid electrophile-mediated protein damage that occurs during oxidative stress requires a comprehensive analysis of electrophile targets adducted under pathophysiological conditions. Incorporation of ω -alkynyl linoleic acid into the phospholipids of macrophages prior to activation by Kdo₂-lipid A, followed by protein extraction, click chemistry, and streptavidin affinity capture, enabled a systems-level survey of proteins adducted by lipid electrophiles generated endogenously during the inflammatory response. Results revealed a dramatic enrichment for membrane and mitochondrial proteins as targets for adduction. A marked decrease in adduction in the presence of MitoTEMPO demonstrated a primary role for mitochondrial superoxide in electrophile generation and indicated an important role for mitochondria as both a source and target of lipid electrophiles, a finding that has not been revealed by prior studies using exogenously provided electrophiles.

Original language	English (US)
Pages (from-to)	2062-2069
Number of pages	8
Journal	ACS Chemical Biology
Volume	12
Issue number	8
DOIs	https://doi.org/10.1021/acschembio.7b00480
State	Published - Aug 18 2017
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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Beavers, W. N., Rose, K. L., Galligan, J. J., Mitchener, M. M., Rouzer, C. A., Tallman, K. A., Lamberson, C. R., Wang, X., Hill, S., Ivanova, P. T., Brown, H. A., Zhang, B., Porter, N. A., & Marnett, L. J. (2017). Protein Modification by Endogenously Generated Lipid Electrophiles: Mitochondria as the Source and Target. ACS Chemical Biology, 12(8), 2062-2069. https://doi.org/10.1021/acschembio.7b00480

Beavers, WN, Rose, KL, Galligan, JJ, Mitchener, MM, Rouzer, CA, Tallman, KA, Lamberson, CR, Wang, X, Hill, S, Ivanova, PT, Brown, HA, Zhang, B, Porter, NA & Marnett, LJ 2017, 'Protein Modification by Endogenously Generated Lipid Electrophiles: Mitochondria as the Source and Target', ACS Chemical Biology, vol. 12, no. 8, pp. 2062-2069. https://doi.org/10.1021/acschembio.7b00480

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title = "Protein Modification by Endogenously Generated Lipid Electrophiles: Mitochondria as the Source and Target",

abstract = "Determining the impact of lipid electrophile-mediated protein damage that occurs during oxidative stress requires a comprehensive analysis of electrophile targets adducted under pathophysiological conditions. Incorporation of ω -alkynyl linoleic acid into the phospholipids of macrophages prior to activation by Kdo2-lipid A, followed by protein extraction, click chemistry, and streptavidin affinity capture, enabled a systems-level survey of proteins adducted by lipid electrophiles generated endogenously during the inflammatory response. Results revealed a dramatic enrichment for membrane and mitochondrial proteins as targets for adduction. A marked decrease in adduction in the presence of MitoTEMPO demonstrated a primary role for mitochondrial superoxide in electrophile generation and indicated an important role for mitochondria as both a source and target of lipid electrophiles, a finding that has not been revealed by prior studies using exogenously provided electrophiles.",

author = "Beavers, {William N.} and Rose, {Kristie L.} and Galligan, {James J.} and Mitchener, {Michelle M.} and Rouzer, {Carol A.} and Tallman, {Keri A.} and Lamberson, {Connor R.} and Xiaojing Wang and Salisha Hill and Ivanova, {Pavlina T.} and Brown, {H. Alex} and Bing Zhang and Porter, {Ned A.} and Marnett, {Lawrence J.}",

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doi = "10.1021/acschembio.7b00480",

language = "English (US)",

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T2 - Mitochondria as the Source and Target

AU - Beavers, William N.

AU - Rose, Kristie L.

AU - Galligan, James J.

AU - Mitchener, Michelle M.

AU - Rouzer, Carol A.

AU - Tallman, Keri A.

AU - Lamberson, Connor R.

AU - Wang, Xiaojing

AU - Hill, Salisha

AU - Ivanova, Pavlina T.

AU - Brown, H. Alex

AU - Zhang, Bing

AU - Porter, Ned A.

AU - Marnett, Lawrence J.

PY - 2017/8/18

Y1 - 2017/8/18

N2 - Determining the impact of lipid electrophile-mediated protein damage that occurs during oxidative stress requires a comprehensive analysis of electrophile targets adducted under pathophysiological conditions. Incorporation of ω -alkynyl linoleic acid into the phospholipids of macrophages prior to activation by Kdo2-lipid A, followed by protein extraction, click chemistry, and streptavidin affinity capture, enabled a systems-level survey of proteins adducted by lipid electrophiles generated endogenously during the inflammatory response. Results revealed a dramatic enrichment for membrane and mitochondrial proteins as targets for adduction. A marked decrease in adduction in the presence of MitoTEMPO demonstrated a primary role for mitochondrial superoxide in electrophile generation and indicated an important role for mitochondria as both a source and target of lipid electrophiles, a finding that has not been revealed by prior studies using exogenously provided electrophiles.

AB - Determining the impact of lipid electrophile-mediated protein damage that occurs during oxidative stress requires a comprehensive analysis of electrophile targets adducted under pathophysiological conditions. Incorporation of ω -alkynyl linoleic acid into the phospholipids of macrophages prior to activation by Kdo2-lipid A, followed by protein extraction, click chemistry, and streptavidin affinity capture, enabled a systems-level survey of proteins adducted by lipid electrophiles generated endogenously during the inflammatory response. Results revealed a dramatic enrichment for membrane and mitochondrial proteins as targets for adduction. A marked decrease in adduction in the presence of MitoTEMPO demonstrated a primary role for mitochondrial superoxide in electrophile generation and indicated an important role for mitochondria as both a source and target of lipid electrophiles, a finding that has not been revealed by prior studies using exogenously provided electrophiles.

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Protein Modification by Endogenously Generated Lipid Electrophiles: Mitochondria as the Source and Target

Abstract

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