ER–mitochondria contacts promote mitochondrial-derived compartment biogenesis

Abstract

Mitochondria are dynamic organelles with essential roles in signaling and metabolism. We recently identified a cellular structure called the mitochondrial-derived compartment (MDC) that is generated from mitochondria in response to amino acid overabundance stress. How cells form MDCs is unclear. Here, we show that MDCs are dynamic structures that form and stably persist at sites of contact between the ER and mitochondria. MDC biogenesis requires the ER–mitochondria encounter structure (ERMES) and the conserved GTPase Gem1, factors previously implicated in lipid exchange and membrane tethering at ER–mitochondria contacts. Interestingly, common genetic suppressors of abnormalities displayed by ERMES mutants exhibit distinct abilities to rescue MDC formation in ERMES-depleted strains and are incapable of rescuing MDC formation in cells lacking Gem1. Thus, the function of ERMES and Gem1 in MDC biogenesis may extend beyond their conventional role in maintaining mitochondrial phospholipid homeostasis. Overall, this study identifies an important function for ER–mitochondria contacts in the biogenesis of MDCs.

Amino Acids Promote Mitochondrial-Derived Compartment Formation in Mammalian Cells

“…Interestingly, we observed that MDC-like structures that had been released from the mitochondrial network remained associated with the ER, suggesting a stable interaction between these two cellular compartments (Figure 4A and Figure 4 Supplement 1A). In line with this observation, we recently found that MDCs form at mitochondria-ER contact sites in yeast and remain associated with the ER over extended periods (English et al, 2020). By contrast, only about 20% of all Tomm70A-enriched domains associated with lysosomes (Figure 4B-C and Figure 4 Supplement 1B) and a very small fraction associated with EEA1-TagRFP labeled endosomes or Pex14 labeled peroxisomes (Figure 4B-C and Figure 4 Supplement 1C-D).…”

“…In yeast, mitochondria are linked to the ER via the ER-mitochondria encounter structure (ERMES) (Kornmann et al, 2011, 2009) and we recently showed that ERMES and its associated GTPase Gem1 are required for MDC formation (English et al, 2020). We thus tested if the Gem1 orthologs Miro1 and Miro2 (Fransson et al, 2003) are required for formation of the Tom70A-enriched structures we identified in mammalian cells.…”

“…It is made The copyright holder for this preprint this version posted December 23, 2020. ; https://doi.org/10.1101/2020.12.23.424218 doi: bioRxiv preprint complex (Kornmann et al, 2011), which facilitates lipid exchange between mitochondria and the ER (Kawano et al, 2018;Kojima et al, 2016). However, ERMES is not completely conserved in mammalian cells (Herrera-Cruz and Simmen, 2017), and lipid transport between mitochondria and the ER seems to be dispensable for MDC formation in yeast (English et al, 2020), raising the possibility that Miro1 and Gem1 may play a more direct role in MDC formation. One possible scenario is that Gem1 in yeast and Miro1 in mammals promote MDC formation by connecting mitochondria to the cytoskeleton.…”

“…In yeast, mitochondria are linked to the ER via the ER-mitochondria encounter structure (ERMES) (Kornmann et al, 2011(Kornmann et al, , 2009 and we recently showed that ERMES and its associated GTPase Gem1 are required for MDC formation (English et al, 2020).…”

“…MDCs are generated during cellular aging (Hughes et al, 2016) and in response to numerous insults that impair cellular amino acid homeostasis including defects in vacuolar amino acid compartmentation, inhibition of protein translation, and activation of amino acid acquisition programs in nutrient-replete conditions (Schuler et al, 2020). In response to amino acid elevation, MDCs form at contact sites between mitochondria and the ER in a manner dependent on the conserved mitochondrial outer membrane GTPase Gem1 (English et al, 2020). Upon formation, MDCs selectively sequester nutrient transporters of the SLC25A family and their associated import receptor Tom70 away from mitochondria, thereby providing cells with a mechanism to limit the abundance of nutrient transporters on mitochondria in response to amino acid excess (Schuler et al, 2020).…”