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  Is a corresponding author
  1. Fred Hutchinson Cancer Research Center, United States
  2. University of Utah School of Medicine, United States

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

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    dang@calicolabs.com
    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

  • 9,543
    Page views
  • 2,474
    Downloads
  • 82
    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)

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

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

  1. Adam L Hughes
  2. Casey E Hughes
  3. Kiersten A Henderson
  4. Nina Yazvenko
  5. Daniel E Gottschling
(2016)
Selective sorting and destruction of mitochondrial membrane proteins in aged yeast
eLife 5:e13943.
https://doi.org/10.7554/eLife.13943

Further reading

    1. Cell Biology
    2. Developmental Biology
    Yalda Afshar, Feyiang Ma ... Luisa Iruela-Arispe
    Research Article

    Environmental cues, such as physical forces and heterotypic cell interactions play a critical role in cell function, yet their collective contributions to transcriptional changes are unclear. Focusing on human endothelial cells, we performed broad individual sample analysis to identify transcriptional drifts associated with environmental changes that were independent of genetic background. Global gene expression profiling by RNAseq and protein expression by LC-MS directed proteomics distinguished endothelial cells in vivo from genetically matched culture (in vitro) samples. Over 43% of the transcriptome was significantly changed by the in vitro environment. Subjecting cultured cells to long-term shear stress significantly rescued the expression of approximately 17% of genes. Inclusion of heterotypic interactions by co-culture of endothelial cells with smooth muscle cells normalized approximately 9% of the original in vivo signature. We also identified novel flow dependent genes, as well as genes that necessitate heterotypic cell interactions to mimic the in vivo transcriptome. Our findings highlight specific genes and pathways that rely on contextual information for adequate expression from those that are agnostic of such environmental cues.

    1. Structural Biology and Molecular Biophysics
    2. Cell Biology
    Peter R Strege, Luke M Cowan ... Arthur Beyder
    Research Article Updated

    Voltage-gated ion channels (VGICs) orchestrate electrical activities that drive mechanical functions in contractile tissues such as the heart and gut. In turn, contractions change membrane tension and impact ion channels. VGICs are mechanosensitive, but the mechanisms of mechanosensitivity remain poorly understood. Here, we leverage the relative simplicity of NaChBac, a prokaryotic voltage-gated sodium channel from Bacillus halodurans, to investigate mechanosensitivity. In whole-cell experiments on heterologously transfected HEK293 cells, shear stress reversibly altered the kinetic properties of NaChBac and increased its maximum current, comparably to the mechanosensitive eukaryotic sodium channel NaV1.5. In single-channel experiments, patch suction reversibly increased the open probability of a NaChBac mutant with inactivation removed. A simple kinetic mechanism featuring a mechanosensitive pore opening transition explained the overall response to force, whereas an alternative model with mechanosensitive voltage sensor activation diverged from the data. Structural analysis of NaChBac identified a large displacement of the hinged intracellular gate, and mutagenesis near the hinge diminished NaChBac mechanosensitivity, further supporting the proposed mechanism. Our results suggest that NaChBac is overall mechanosensitive due to the mechanosensitivity of a voltage-insensitive gating step associated with the pore opening. This mechanism may apply to eukaryotic VGICs, including NaV1.5.