@article{949ed20f58114676b94d9c13a5e5e95a,
title = "Impaired phosphatidylethanolamine metabolism activates a reversible stress response that detects and resolves mutant mitochondrial precursors",
abstract = "Phosphatidylethanolamine (PE) made in mitochondria has long been recognized as an important precursor for phosphatidylcholine production that occurs in the endoplasmic reticulum (ER). Recently, the strict mitochondrial localization of the enzyme that makes PE in the mitochondrion, phosphatidylserine decarboxylase 1 (Psd1), was questioned. Since a dual localization of Psd1 to the ER would have far-reaching implications, we initiated our study to independently re-assess the subcellular distribution of Psd1. Our results support the unavoidable conclusion that the vast majority, if not all, of functional Psd1 resides in the mitochondrion. Through our efforts, we discovered that mutant forms of Psd1 that impair a self-processing step needed for it to become functional are dually localized to the ER when expressed in a PE-limiting environment. We conclude that severely impaired cellular PE metabolism provokes an ER-assisted adaptive response that is capable of identifying and resolving nonfunctional mitochondrial precursors.",
keywords = "Cell Biology, Molecular Physiology, Proteomics",
author = "Sam, {Pingdewinde N.} and Elizabeth Calzada and Acoba, {Michelle Grace} and Tian Zhao and Yasunori Watanabe and Anahita Nejatfard and Trinidad, {Jonathan C.} and Shutt, {Timothy E.} and Neal, {Sonya E.} and Claypool, {Steven M.}",
note = "Funding Information: We would like to thank Drs. Jonathan Friedman (UT Southwestern, USA) and Jodi Nunnari (UC Davis, USA) for sharing W303-JF WT and Δpsd1 strains, Drs. Susan Michaelis (JHMI, USA), George Carman (Rutgers University, USA), and Carla Koehler (UCLA, USA) for antibodies, Dr. Hilla Weidberg (University of British Columbia, Canada) for sharing her protocol for detecting CIS1 transcript levels, and Linhao Ruan and Drs. Selvaraju Kandasamy, Oluwaseun B. Ogunbona, Eric Spear, and Samuel Jayakanthan for technical assistance. This work was supported by the National Institutes of Health (Grant R01GM111548 to S.M.C. and R01GM111548-03S1 to P.N.S.), the National Science Foundation Graduate Research Fellowship Program (DGE1746891 to P.N.S.), a Biochemistry, Cellular, and Molecular Biology Program training grant (T32GM007445 to E.C.), a predoctoral fellowship from the American Heart Association (16PRE31140006 to M.G.A.), the Indiana University Precision Health Grand Challenge Initiative to J.C.T. NIH grant (1R35GM133565 to S.E.N) and Pew Biomedical Award (to S.E.N.), the Japan Society for the Promotion of Science (JSPS) KAKENHI (20K15734 to Y.W.), and the Canadian Institutes of Health Research (T.E.S.). S.M.C conceived the project; P.N.S. E.C. T.Z. A.N. T.S. S.E.N. and S.M.C. designed research, performed experiments, and made strains; P.N.S. M.G.A. and S.M.C. analyzed data; J.C.T performed the mass spectrometry-based proteomics; Y.W. developed and analyzed the homology models of Psd1; and P.N.S. E.C. and S.M.C. wrote the paper with the feedback and approval from all authors. The authors declare no competing interests. One or more of the authors of this paper self-identify as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Funding Information: We would like to thank Drs. Jonathan Friedman (UT Southwestern, USA) and Jodi Nunnari (UC Davis, USA) for sharing W303-JF WT and Δpsd1 strains, Drs. Susan Michaelis (JHMI, USA), George Carman (Rutgers University, USA), and Carla Koehler (UCLA, USA) for antibodies, Dr. Hilla Weidberg (University of British Columbia, Canada) for sharing her protocol for detecting CIS1 transcript levels, and Linhao Ruan and Drs. Selvaraju Kandasamy, Oluwaseun B. Ogunbona, Eric Spear, and Samuel Jayakanthan for technical assistance. This work was supported by the National Institutes of Health (Grant R01GM111548 to S.M.C. and R01GM111548-03S1 to P.N.S.), the National Science Foundation Graduate Research Fellowship Program ( DGE1746891 to P.N.S.), a Biochemistry, Cellular, and Molecular Biology Program training grant ( T32GM007445 to E.C.), a predoctoral fellowship from the American Heart Association ( 16PRE31140006 to M.G.A.), the Indiana University Precision Health Grand Challenge Initiative to J.C.T., NIH grant ( 1R35GM133565 to S.E.N) and Pew Biomedical Award (to S.E.N.), the Japan Society for the Promotion of Science (JSPS) KAKENHI ( 20K15734 to Y.W.), and the Canadian Institutes of Health Research (T.E.S.). Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = mar,
day = "19",
doi = "10.1016/j.isci.2021.102196",
language = "English (US)",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "3",
}