Menu

Close

ER-Mitochondria Contacts Promote Mitochondrial-Derived Compartment Biogenesis

Alyssa M. English, Benoît Kornmann, Janet M. Shaw, Adam L. Hughes

Preprint posted on March 14, 2020 https://www.biorxiv.org/content/10.1101/2020.03.13.991133v1

and

Mitochondrial-Derived Compartments Facilitate Cellular Adaptation to Amino Acid Stress

Max-Hinderk Schuler, Alyssa M. English, Thane J. Campbell, Janet M. Shaw, Adam L. Hughes

Preprint posted on March 14, 2020 https://www.biorxiv.org/content/10.1101/2020.03.13.991091v1

How to deal with and compartmentalize stress: mitochondria utilize a selective compartment to combat amino acid overload.

Selected by Berrak Ugur

Categories: cell biology

Background:

 Mitochondria are important for a number of metabolic processes including ATP production, lipid catabolism, amino acid metabolism and iron homeostasis (Ernster and Schatz, 1981). Therefore, cellular metabolic cues are tightly communicated to mitochondria and several homeostatic pathways are evolved to ensure mitochondrial health. Previously, Hughes and colleagues (Hughes et al., 2016) described a degradation system to selectively sort and degrade mitochondrial proteins without disrupting mitochondrial integrity in aging yeast cells. They termed this autophagy and mitochondrial fission dependent structure as mitochondrial derived compartments (MDC, Video1). Moreover, they showed that these compartments selectively sort mitochondrial outer membrane protein TOM70 and solute carrier family (SLC25) proteins that are translocated by TOM70. However, how these proteins are selectively incorporated to MDCs or the insults that result in MDC formation remains a mystery.

Video1: MDCs in aged yeast cells. Small mitochondrial vesicle-like fragments (green) are present outside of fragmented vacuole (red). In the middle of the movie, vacuole becomes transparent so that mitochondria inside the vacuole is visible. Blue staining in the beginning shows budscars that indicate the old age of the cell. Hughes et al., 2016. DOI: 10.7554/eLife.13943.004

A similar mitochondrial‐vesicle transport system has been previously described (reviewed in Sugiura et al., 2014). These 70-150 nm sized mitochondria derived vesicles (MDVs) were shown to selectively sort and traffic cargo to either lysosomes or peroxisomes (Neuspiel et al, 2008, Soubannier et al, 2012a, b). However, unlike MDCs, MDVs were shown not to depend on mitochondrial fission (Neuspiel et al, 2008; Soubannier et al, 2012a, b). Instead, mitochondria derived vesicles were regulated by mitophagy related proteins. Overall, there seems to be distinct sorting mechanisms to selectively traffic mitochondrial cargo to target organelles.

Key Findings:

 In two back to back preprints, the Hughes lab further explored the formation and dynamics of Mitochondria-derived compartments (MDCs). First, they showed that MDCs are dynamic, micron-sized organelles stably formed at ER-mitochondria sites. Next, they asked if the ER-mitochondria contact sites are important for the formation of these compartments. ER-mitochondria contact sites are regulated by various proteins one of which is a special yeast structure called ER-mitochondria encounter structure (ERMES, Kornmann et al., 2009). ERMES tethers ER and mitochondria and it is important for various mitochondrial functions including Ca2+ and mitochondrial lipid homeostasis (Kornmann and Walter, 2010). To address if ERMES plays a role in MDC formation, the authors tested if ERMES mutant strains are able to form MDCs. In addition, they also assessed MDC formation in ERMES regulator GTPase, Gem1 (Kornmann et al., 2011) mutants. After inducing MDCs in response to various stress conditions, the author showed that neither ERMES nor Gem1 mutants are able to form MDCs. Interestingly, they described that the role of ERMES/Gem1 in MDC formation is not linked to their known function in mitochondrial phospholipid homeostasis, indicating a novel, noncanonical ERMES/Gem1 function is important for compartment formation.

To understand the mitochondrial signal that leads to MDC formation, the authors tested various mitochondrial insults and showed that MDC are formed due to increased amino acid levels. Specifically, addition of Leucine, its derivatives and other branched chain amino acids were sufficient to induce MDC formation. Interestingly, a known nutrient sensing pathway did not induce MDC formation. They showed that the nutrient transporter levels within mitochondria regulated MDC formation. In the absence of MDC formation cells grew normally, indicating that there is a redundant pathway to balance amino acid toxicity. The authors showed that MDCs act in parallel to endosomal sorting complexes required for transport (ESCRT) pathway to regulate amino acid homeostasis. Overall, these two studies unravel that an increase in amino acids levels may be regulated through a selective mitochondrial degradation pathway.

 Take home messages

  • Mitochondrial-derived compartments are micron-sized, lumen-containing organelles that form at sites of contact between the ER and mitochondria in response to branched chain amino acid stress.
  • Mitochondrial-derived compartment biogenesis requires a noncanonical function of the ERMES complex and the conserved GTPase Gem1.
  • Mitochondrial-derived compartments are not linked to the role of ERMES/Gem1 in the maintenance of mitochondrial phospholipids.

What I liked about these studies:

 Mitochondria derived compartments display yet another way of mitochondria protecting itself from cellular insults. I am curious to see if this pathway has a mammalian counterpart but more interested in seeing what additional function of ER-mitochondria contact sites are required for the formation of these compartments.

Open Questions: 

  1. Is it possible that the MDC formation is related to mitochondrial derived vesicles? It seems like autophagy is important for the degradation of MDCs but are not required for the formation. Especially considering that the initial formation of MDC’s do not depend on autophagy suggest that they may be linked to MDVs.
  2. The original paper (Hughes et al., 2016) suggests that MDCs are induced by aging. Do aged yeast cells have increased amino acid levels? In another study, it was shown that additional supplemental leucine extends the chronological longevity of both wild type and autophagy-deficient yeast cells (Alvers et al., 2009). How do you think that chronological longevity is linked to MDC pathway?
  3. Do you have any speculations as to what role(s) ERMES/Gem1 and the ER have in MDC formation?

References:

Alvers AL, Fishwick LK, Wood MS, Hu D, Chung HS, Dunn WA Jr, Aris JP. Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae. Aging Cell. 2009

Ernster L, Schatz G. Mitochondria: a historical review. J Cell Biol. 1981

Hughes AL, Hughes CE, Henderson KA, Yazvenko N, Gottschling DE. Selective sorting and destruction of mitochondrial membrane proteins in aged yeast. Elife. 2016.

Kornmann B, Currie E, Collins SR, Schuldiner M, Nunnari J, Weissman JS, Walter. An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science. 2009

Kornmann B, Walter P. ERMES-mediated ER-mitochondria contacts: molecular hubs for the regulation of mitochondrial biology. J Cell Sci. 2010

Kornmann B, Osman C, Walter P. The conserved GTPase Gem1 regulates endoplasmic reticulum-mitochondria connections. Proc Natl Acad Sci U S A. 2011

Neuspiel M, Schauss AC, Braschi E, Zunino R, Rippstein P, Rachubinski RA, Andrade-Navarro MA, McBride HM. Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers. Curr Biol. 2008

Soubannier V, McLelland GL, Zunino R, Braschi E, Rippstein P, Fon EA, McBride. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr Biol. 2012a

Soubannier V, Rippstein P, Kaufman BA, Shoubridge EA, McBride HM. Reconstitution of mitochondria derived vesicle formation demonstrates selective enrichment of oxidized cargo. PLoS One. 2012b

Sugiura A, McLelland GL, Fon EA, McBride HM. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. EMBO J. 2014

 

Tags: aging, lysosome, metabolism, mitochondria

Posted on: 8th April 2020 , updated on: 14th April 2020

doi: https://doi.org/10.1242/prelights.18256

(1 votes)




Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the cell biology category:

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

 



List by Gautam Dey, Samantha Seah

1

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka, Madhuja Samaddar, Miguel V. Almeida, Sejal Davla, Jennifer Ann Black, Gautam Dey

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Preprint missing? Don't hesitate to let us know.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar, Ramona Jühlen, Amanda Haage, Laura McCormick, Maiko Kitaoka

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Gautam Dey

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Gautam Dey

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA

 



List by Joseph Jose Thottacherry

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.

 



List by Gautam Dey, Amanda Haage
Close