1. Cell Biology
Download icon

Selective sorting and destruction of mitochondrial membrane proteins in aged yeast

  1. Adam L Hughes  Is a corresponding author
  2. Casey E Hughes
  3. Kiersten A Henderson
  4. Nina Yazvenko
  5. Daniel E Gottschling
  1. Fred Hutchinson Cancer Research Center, United States
  2. University of Utah School of Medicine, United States
  3. Calico Life Sciences, United States
Research Article
  • Cited 62
  • Views 8,601
  • Annotations
Cite this article as: eLife 2016;5:e13943 doi: 10.7554/eLife.13943

Abstract

Mitochondrial dysfunction is a hallmark of aging, and underlies the development of many diseases. Cells maintain mitochondrial homeostasis through a number of pathways that remodel the mitochondrial proteome or alter mitochondrial content during times of stress or metabolic adaptation. Here, using yeast as a model system, we identify a new mitochondrial degradation system that remodels the mitochondrial proteome of aged cells. Unlike many common mitochondrial degradation pathways, this system selectively removes a subset of membrane proteins from the mitochondrial inner and outer membranes, while leaving the remainder of the organelle intact. Selective removal of preexisting proteins is achieved by sorting into a mitochondrial-derived compartment, or MDC, followed by release through mitochondrial fission and elimination by autophagy. Formation of MDCs requires the import receptors Tom70/71, and failure to form these structures exacerbates preexisting mitochondrial dysfunction, suggesting that the MDC pathway provides protection to mitochondria in times of stress.

Article and author information

Author details

  1. Adam L Hughes

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    hughes@biochem.utah.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Casey E Hughes

    Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kiersten A Henderson

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nina Yazvenko

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Daniel E Gottschling

    Calico Life Sciences, South San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Andrew Dillin, Howard Hughes Medical Institute, University of California, Berkeley, United States

Publication history

  1. Received: December 19, 2015
  2. Accepted: April 18, 2016
  3. Accepted Manuscript published: April 20, 2016 (version 1)
  4. Accepted Manuscript updated: April 25, 2016 (version 2)
  5. Version of Record published: June 1, 2016 (version 3)

Copyright

© 2016, Hughes et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 8,601
    Page views
  • 2,334
    Downloads
  • 62
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

  1. Further reading

Further reading

    1. Cell Biology
    Dawei Wang et al.
    Research Article Updated

    Actin filaments (F-actin) have been implicated in various steps of endosomal trafficking, and the length of F-actin is controlled by actin capping proteins, such as CapZ, which is a stable heterodimeric protein complex consisting of α and β subunits. However, the role of these capping proteins in endosomal trafficking remains elusive. Here, we found that CapZ docks to endocytic vesicles via its C-terminal actin-binding motif. CapZ knockout significantly increases the F-actin density around immature early endosomes, and this impedes fusion between these vesicles, manifested by the accumulation of small endocytic vesicles in CapZ-knockout cells. CapZ also recruits several RAB5 effectors, such as Rabaptin-5 and Rabex-5, to RAB5-positive early endosomes via its N-terminal domain, and this further activates RAB5. Collectively, our results indicate that CapZ regulates endosomal trafficking by controlling actin density around early endosomes and recruiting RAB5 effectors.

    1. Cell Biology
    2. Structural Biology and Molecular Biophysics
    Carolina Franco Nitta et al.
    Research Article Updated

    Crosstalk between different receptor tyrosine kinases (RTKs) is thought to drive oncogenic signaling and allow therapeutic escape. EGFR and RON are two such RTKs from different subfamilies, which engage in crosstalk through unknown mechanisms. We combined high-resolution imaging with biochemical and mutational studies to ask how EGFR and RON communicate. EGF stimulation promotes EGFR-dependent phosphorylation of RON, but ligand stimulation of RON does not trigger EGFR phosphorylation – arguing that crosstalk is unidirectional. Nanoscale imaging reveals association of EGFR and RON in common plasma membrane microdomains. Two-color single particle tracking captured formation of complexes between RON and EGF-bound EGFR. Our results further show that RON is a substrate for EGFR kinase, and that transactivation of RON requires formation of a signaling competent EGFR dimer. These results support a role for direct EGFR/RON interactions in propagating crosstalk, such that EGF-stimulated EGFR phosphorylates RON to activate RON-directed signaling.