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Mitochondrial protein import is regulated by p17/PERMIT to mediate lipid metabolism and cellular stress. Sci Adv 2019 09;5(9):eaax1978

Date

09/20/2019

Pubmed ID

31535025

Pubmed Central ID

PMC6739097

DOI

10.1126/sciadv.aax1978

Abstract

How lipid metabolism is regulated at the outer mitochondrial membrane (OMM) for transducing stress signaling remains largely unknown. We show here that this process is controlled by trafficking of ceramide synthase 1 (CerS1) from the endoplasmic reticulum (ER) to the OMM by a previously uncharacterized p17, which is now renamed protein that mediates ER-mitochondria trafficking (PERMIT). Data revealed that p17/PERMIT associates with newly translated CerS1 on the ER surface to mediate its trafficking to the OMM. Cellular stress induces Drp1 nitrosylation/activation, releasing p17/PERMIT to retrieve CerS1 for its OMM trafficking, resulting in mitochondrial ceramide generation, mitophagy and cell death. In vivo, CRISPR-Cas9-dependent genetic ablation of p17/PERMIT prevents acute stress-mediated CerS1 trafficking to OMM, attenuating mitophagy in p17/PERMIT-/- mice, compared to controls, in various metabolically active tissues, including brain, muscle, and pancreas. Thus, these data have implications in diseases associated with accumulation of damaged mitochondria such as cancer and/or neurodegeneration.

Author List

Oleinik N, Kim J, Roth BM, Selvam SP, Gooz M, Johnson RH, Lemasters JJ, Ogretmen B

Author

Roger H. Johnson PhD Associate Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
CRISPR-Cas Systems
Ceramides
Endoplasmic Reticulum
Humans
Lipid Metabolism
Membrane Proteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
Mitochondrial Membranes
Mitochondrial Proteins
Protein Transport
Sphingosine N-Acyltransferase
Stress, Physiological