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

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

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