ER fatalities-The role of ER-mitochondrial contact sites in yeast life and death decisions

Abstract

Following extracellular stress signals, all eukaryotic cells choose whether to elicit a pro-survival or pro-death response. The decision over which path to take is governed by the severity and duration of the damage. In response to mild stress, pro-survival programs are initiated (unfolded protein response, autophagy, mitophagy) whereas severe or chronic stress forces the cell to abandon these adaptive programs and shift towards regulated cell death to remove irreversibly damaged cells. Both pro-survival and pro-death programs involve regulated communication between the endoplasmic reticulum (ER) and mitochondria. In yeast, recent data suggest this inter-organelle contact is facilitated by the endoplasmic reticulum mitochondria encounter structure (ERMES). These membrane contacts are not only important for the exchange of cellular signals, but also play a role in mitochondrial tethering during mitophagy, mitochondrial fission and mitochondrial inheritance. This review focuses on recent findings in yeast that shed light on how ER-mitochondrial communication mediates critical cell fate decisions.

Keywords: ERMES; Endoplasmic reticulum; Mitochondria; Mitophagy; Programmed cell death; Signal transduction.

Figure 1

Following stress cells have to decide whether to elicit a pro-life or a pro-death response. The ER-Mitochondrial interface co-ordinates this decision.

Figure 2

Topology of the ERMES complex at the ER-mitochondria contact site. Mdm34 and Mdm10 are embedded in the mitochondrial outer membrane, as is the regulatory GTPase Gem1. Mmm1 is an ER protein and is bridged to the mitochondrial components by the cytosolic Mdm12. Mmm1, Mdm12 and Mdm34 all contain SMP domains. Modified from [32].

Figure 3

Molecular mechanisms of mitophagy in yeast. Mitophagy is induced upon CK2 mediated phosphorylation of Atg32. This event triggers the Atg32-Atg11 receptor-adaptor interaction and recruits the mitochondria to the pre-autophagosomal structure/phagophore assembly site (PAS). Subsequently the Atg8-Atg32 interaction anchors the mitochondria on the isolation membrane (IM) which also facilitates the formation of the autophagosome surrounding the mitochondria. Atg8 also interacts with the ERMES member Mmm1, thereby tethering the mitochondria to the ER. This interaction also supplies lipids from the endoplasmic reticulum (blue ring) for extension of the isolation membrane and thereby facilitates mitophagy.

Figure 4

Autophagy induction in yeast. Under nutrient-rich condition, the activation of both the mTOR1 and PKA pathways results in Atg13 phosphorylation. This in turn inhibits the formation of the Atg1 complex and formation of the pre-autophagosomal structure (PAS). PKA and SCH9 pathways also inhibit the expression of the kinase Rim15. Rim15 activity is needed to upregulate genes needed for mitophagy. In addition under nutrient-rich conditions the HOG1 and CWI pathways are not activated. When mitophagy is induced (see text for details) the mTOR1, PKA and SCH9 pathways are inactivated. The resulting dephosphorylated Atg13 can consequently associated with the Atg1 complex. Also inactivation of PKA and SCH9 leads to Rim15 activation and upregulation of ATG specific genes. The HOG1 and CWI pathways are also activated which leads to activation of CK2 and an unknown kinase.