1. Cell Biology

MICOS coordinates with respiratory complexes and lipids to establish mitochondrial inner membrane architecture

  1. Jonathan R Friedman
  2. Arnaud Mourier
  3. Justin Yamada
  4. J Michael McCaffery
  5. Jodi Nunnari  Is a corresponding author
  1. University of California, Davis, United States
  2. Max Planck Institute for Biology of Ageing, Germany
  3. Johns Hopkins University, United States
https://doi.org/10.7554/eLife.07739
Share this article
Cite this article
  1. Jonathan R Friedman
  2. Arnaud Mourier
  3. Justin Yamada
  4. J Michael McCaffery
  5. Jodi Nunnari
(2015)
MICOS coordinates with respiratory complexes and lipids to establish mitochondrial inner membrane architecture
eLife 4:e07739.
https://doi.org/10.7554/eLife.07739
  2. Download BibTeX
  3. Download .RIS

Abstract

The conserved MICOS complex functions as a primary determinant of mitochondrial inner membrane structure. We address the organization and functional roles of MICOS and identify two independent MICOS subcomplexes: Mic27/Mic10/Mic12, whose assembly is dependent on respiratory complexes and the mitochondrial lipid cardiolipin, and Mic60/Mic19, which assembles independent of these factors. Our data suggest that MICOS subcomplexes independently localize to cristae junctions and are connected via Mic19, which functions to regulate subcomplex distribution, and thus, potentially also cristae junction copy number. MICOS subunits have non-redundant functions as the absence of MICOS subcomplexes results in more severe morphological and respiratory growth defects than deletion of single MICOS subunits or subcomplexes. Mitochondrial defects resulting from MICOS loss are caused by misdistribution of respiratory complexes in the inner membrane. Together, our data are consistent with a model where MICOS, mitochondrial lipids and respiratory complexes coordinately build a functional and correctly shaped mitochondrial inner membrane.

Article and author information

Author details

  1. Jonathan R Friedman

    Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.

  2. Arnaud Mourier

    Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    No competing interests declared.

  3. Justin Yamada

    Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.

  4. J Michael McCaffery

    Integrated Imaging Center, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  5. Jodi Nunnari

    Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, United States
    For correspondence
    jmnunnari@ucdavis.edu
    Competing interests
    Jodi Nunnari, Reviewing editor, eLife On Scientific Advisory Board of Mitobridge, and declares no financial interest related to this work..

Copyright

© 2015, Friedman 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

  • 7,362
    views
  • 1,976
    downloads
  • 221
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Jonathan R Friedman
  2. Arnaud Mourier
  3. Justin Yamada
  4. J Michael McCaffery
  5. Jodi Nunnari
(2015)
MICOS coordinates with respiratory complexes and lipids to establish mitochondrial inner membrane architecture
eLife 4:e07739.
https://doi.org/10.7554/eLife.07739

Share this article

https://doi.org/10.7554/eLife.07739

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Binding of LncDACH1 to dystrophin impairs the membrane trafficking of Nav1.5 protein and increases ventricular arrhythmia susceptibility

    Genlong Xue, Jiming Yang ... Zhenwei Pan
    Research Article

    Dystrophin is a critical interacting protein of Nav1.5 that determines its membrane anchoring in cardiomyocytes. Long noncoding RNAs (lncRNAs) are involved in the regulation of cardiac ion channels, while their influence on sodium channels remains unexplored. Our preliminary data showed that lncRNA-Dachshund homolog 1 (lncDach1) can bind to dystrophin, which drove us to investigate if lncDach1 can regulate sodium channels by interfering with dystrophin. Western blot and immunofluorescent staining showed that cardiomyocyte-specific transgenic overexpression of lncDach1 (lncDach1-TG) reduced the membrane distribution of dystrophin and Nav1.5 in cardiomyocytes. Meanwhile, peak INa was reduced in the hearts of lncDach1-TG mice than wild-type (WT) controls. The opposite data of western blot, immunofluorescent staining and patch clamp were collected from lncDach1 cardiomyocyte conditional knockout (lncDach1-cKO) mice. Moreover, increased ventricular arrhythmia susceptibility was observed in lncDach1-TG mice in vivo and ex vivo. The conservative fragment of lncDach1 inhibited membrane distribution of dystrophin and Nav1.5, and promoted the inducibility of ventricular arrhythmia. Strikingly, activation of Dystrophin transcription by dCas9-SAM system in lncDach1-TG mice rescued the impaired membrane distribution of dystrophin and Nav1.5, and prevented the occurrence of ventricular arrhythmia. Furthermore, lncDach1 was increased in transaortic constriction (TAC) induced failing hearts, which promoted the inducibility of ventricular arrhythmia. And the expression of lncDach1 is regulated by hydroxyacyl-CoA dehydrogenase subunit beta (hadhb), which binds to lncDach1 and decreases its stability. The human homologue of lncDACH1 inhibited the membrane distribution of Nav1.5 in human iPS-differentiated cardiomyocytes. The findings provide novel insights into the mechanism of Nav1.5 membrane targeting and the development of ventricular arrhythmias.

    1. Cell Biology

    Noncanonical roles of ATG5 and membrane atg8ylation in retromer assembly and function

    Masroor Ahmad Paddar, Fulong Wang ... Vojo Deretic
    Research Article

    ATG5 is one of the core autophagy proteins with additional functions such as noncanonical membrane atg8ylation, which among a growing number of biological outputs includes control of tuberculosis in animal models. Here, we show that ATG5 associates with retromer’s core components VPS26, VPS29, and VPS35 and modulates retromer function. Knockout of ATG5 blocked trafficking of a key glucose transporter sorted by the retromer, GLUT1, to the plasma membrane. Knockouts of other genes essential for membrane atg8ylation, of which ATG5 is a component, affected GLUT1 sorting, indicating that membrane atg8ylation as a process affects retromer function and endosomal sorting. The contribution of membrane atg8ylation to retromer function in GLUT1 sorting was independent of canonical autophagy. These findings expand the scope of membrane atg8ylation to specific sorting processes in the cell dependent on the retromer and its known interactors.

    1. Cancer Biology
    2. Cell Biology

    TIPE drives a cancer stem-like phenotype by promoting glycolysis via PKM2/HIF-1α axis in melanoma

    Maojin Tian, Le Yang ... Peiqing Zhao
    Research Article

    TIPE (TNFAIP8) has been identified as an oncogene and participates in tumor biology. However, how its role in the metabolism of tumor cells during melanoma development remains unclear. Here, we demonstrated that TIPE promoted glycolysis by interacting with pyruvate kinase M2 (PKM2) in melanoma. We found that TIPE-induced PKM2 dimerization, thereby facilitating its translocation from the cytoplasm to the nucleus. TIPE-mediated PKM2 dimerization consequently promoted HIF-1α activation and glycolysis, which contributed to melanoma progression and increased its stemness features. Notably, TIPE specifically phosphorylated PKM2 at Ser 37 in an extracellular signal-regulated kinase (ERK)-dependent manner. Consistently, the expression of TIPE was positively correlated with the levels of PKM2 Ser37 phosphorylation and cancer stem cell (CSC) markers in melanoma tissues from clinical samples and tumor bearing mice. In summary, our findings indicate that the TIPE/PKM2/HIF-1α signaling pathway plays a pivotal role in promoting CSC properties by facilitating the glycolysis, which would provide a promising therapeutic target for melanoma intervention.