@article{a897af9ce75d4105b110a7e9a976e4f0,
title = "NIX-Mediated Mitophagy Promotes Effector Memory Formation in Antigen-Specific CD8+ T Cells",
abstract = "Autophagy plays a critical role in the maintenance of immunological memory. However, the molecular mechanisms involved in autophagy-regulated effector memory formation in CD8+ T cells remain unclear. Here we show that deficiency in NIX-dependent mitophagy leads to metabolic defects in effector memory T cells. Deletion of NIX caused HIF1α accumulation and altered cellular metabolism from long-chain fatty acid to short/branched-chain fatty acid oxidation, thereby compromising ATP synthesis during effector memory formation. Preventing HIF1α accumulation restored long-chain fatty acid metabolism and effector memory formation in antigen-specific CD8+ T cells. Our study suggests that NIX-mediated mitophagy is critical for effector memory formation in T cells.",
keywords = "CD8 T cells, HIF1α, NIX, autophagy, effector memory cells, fatty acid metabolism, long-chain fatty acid oxidation, mitochondrial superoxide, mitophagy, short/branched-chain fatty acid oxidation",
author = "Gupta, {Shubhranshu S.} and Robert Sharp and Colby Hofferek and Le Kuai and Dorn, {Gerald W.} and Jin Wang and Min Chen",
note = "Funding Information: We thank Jay Dunn for advice on extracellular flux analysis; Albert Jang for technical assistance; Farah Kheradmand, David Corry, Tony Eissa, George Makedonas, Matthew Bettini, and Hana El Sahly for discussions; and Nagireddy Putluri for analyses of short/branched-chain fatty acids. This work was supported by grants from the American Heart Association to M.C ( 15GRNT25700357 ), the Cancer Prevention Research Institute of Texas (CPRIT) to M.C. and J.W. ( RP160384 ), the NIH to J.W. ( R01 AI116644 and R01 AI123221 ) and to G.W.D. ( R35HL135736 ), and the Lupus Research Institute to M.C. and J.W. We acknowledge technical support from Baylor College of Medicine{\textquoteright}s Cytometry and Cell Sorting Core, with funding from the NIH ( P30 AI036211 , P30 CA125123 , and S10 RR024574 ); Integrated Microscopy Core, with funding from the NIH ( DK56338 and CA125123 ) and the CPRIT ( RP150578 ), the Dan L. Duncan Comprehensive Cancer Center (DLDCC), and the John S. Dunn Gulf Coast Consortium for Chemical Genomics ; Mouse Metabolism and Phenotyping Core, with funding from the NIH ( RO1DK114356 and UM1HG006348 ) and CPRIT Core Facility Support Award ( RP170005 ), “Proteomic and Metabolomic Core Facility” with NCI Cancer Center Support Grant ( P30CA125123 ), and DLDCC intramural funds. Funding Information: We thank Jay Dunn for advice on extracellular flux analysis; Albert Jang for technical assistance; Farah Kheradmand, David Corry, Tony Eissa, George Makedonas, Matthew Bettini, and Hana El Sahly for discussions; and Nagireddy Putluri for analyses of short/branched-chain fatty acids. This work was supported by grants from the American Heart Association to M.C (15GRNT25700357), the Cancer Prevention Research Institute of Texas (CPRIT) to M.C. and J.W. (RP160384), the NIH to J.W. (R01 AI116644 and R01 AI123221) and to G.W.D. (R35HL135736), and the Lupus Research Institute to M.C. and J.W. We acknowledge technical support from Baylor College of Medicine's Cytometry and Cell Sorting Core, with funding from the NIH (P30 AI036211, P30 CA125123, and S10 RR024574); Integrated Microscopy Core, with funding from the NIH (DK56338 and CA125123) and the CPRIT (RP150578), the Dan L. Duncan Comprehensive Cancer Center (DLDCC), and the John S. Dunn Gulf Coast Consortium for Chemical Genomics; Mouse Metabolism and Phenotyping Core, with funding from the NIH (RO1DK114356 and UM1HG006348) and CPRIT Core Facility Support Award (RP170005), ?Proteomic and Metabolomic Core Facility? with NCI Cancer Center Support Grant (P30CA125123), and DLDCC intramural funds. S.S.G. R.S. and C.H. performed experiments involving flow cytometry. L.K. performed the thymic T cell development study. S.S.G. analyzed data and performed the rest of the experiments. G.D. generated NIXf/f mice. S.S.G. planned studies, designed experiments, and wrote the manuscript. M.C. and J.W. supervised the study and edited the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = nov,
day = "12",
doi = "10.1016/j.celrep.2019.10.032",
language = "English",
volume = "29",
pages = "1862--1877.e7",
journal = "Cell Reports",
issn = "2211-1247",
number = "7",
}