Mitochondrial protein import is regulated by p17/PERMIT to mediate lipid metabolism and cellular stress

Sci Adv. 2019 Sep 11;5(9):eaax1978. doi: 10.1126/sciadv.aax1978. eCollection 2019 Sep.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Ceramides / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • Humans
  • Lipid Metabolism
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Proteins / antagonists & inhibitors
  • Mitochondrial Proteins / physiology*
  • Mitophagy*
  • Protein Transport
  • Sphingosine N-Acyltransferase / physiology*
  • Stress, Physiological*


  • Ceramides
  • Membrane Proteins
  • Mitochondrial Proteins
  • CerS1 protein, mouse
  • Sphingosine N-Acyltransferase