Impaired phosphatidylethanolamine metabolism activates a reversible stress response that detects and resolves mutant mitochondrial precursors
Pingdewinde N. Sam,
Elizabeth Calzada,
Michelle Grace Acoba,
Tian Zhao,
Yasunori Watanabe,
Anahita Nejatfard,
Jonathan C. Trinidad,
Timothy E. Shutt,
Sonya E. Neal,
Steven M. Claypool
Affiliations
Pingdewinde N. Sam
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Elizabeth Calzada
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Michelle Grace Acoba
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Tian Zhao
Departments of Medical Genetics and Biochemistry & Molecular Biology, Cumming School of Medicine, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
Yasunori Watanabe
Faculty of Science, Yamagata University, 1-4-12 Kojirakawa-machi, Yamagata, Yamagata 990-8560, Japan
Anahita Nejatfard
Division of Biological Sciences, The Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA, USA
Jonathan C. Trinidad
Department of Chemistry, Indiana University, Bloomington, IN, USA
Timothy E. Shutt
Faculty of Science, Yamagata University, 1-4-12 Kojirakawa-machi, Yamagata, Yamagata 990-8560, Japan
Sonya E. Neal
Division of Biological Sciences, The Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA, USA
Steven M. Claypool
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding author
Summary: 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.
