The novel mitochondrial outer membrane protein Mcp3 follows a unique IMP-dependent import pathway

Mitochondria are essential organelles of most eukaryotic cells and are involved in many important cellular activities. The viability of cells greatly depends on proper function of mitochondria, not only because mitochondria are ‘the powerhouse of the cell’, in fact they also play essential roles in metabolic processes and cellular signaling. Many neurological diseases are associated with mitochondrial disorders, illustrating the need to identify new components that participate in maintaining mitochondrial integrity. Mitochondria harbor two membranes, the mitochondrial outer membrane and inner membrane, which both have a characteristic phospholipid composition distinguishing them from all other cellular membranes. Maintenance of cellular and mitochondrial lipid homeostasis depends on membrane contact sites and the exchange of phospholipids between organelles. In yeast, connections between mitochondria and the endoplasmic reticulum (ER) are mediated by the ER-mitochondria encounter structure (ERMES) which has a crucial role in many cellular processes. Defects in ERMES lead to a multitude of phenotypes, but the precise molecular function of the ERMES complex and its subunit Mdm10 (mitochondrial distribution and morphology 10) is still not entirely understood. In order to shed light on this topic we searched for suppressors of the mdm10Δ growth defect and found a novel mitochondrial protein which we named Mcp3 for Mdm10 complementing protein 3. Mcp3 follows a unique biogenesis pathway. It is initially recognized by the mitochondrial import receptor Tom70 and crosses the outer membrane via the translocase of the outer membrane. Mcp3 is then handed over to the translocase of the inner membrane (TIM23) and gets processed by the inner membrane peptidase. Subsequently, mature Mcp3 is released to the intermembrane space and integrates into the outer membrane in a process that possibly involves the mitochondrial import complex. Mcp3 is the first outer membrane protein that is reported to be processed by a peptidase of the inner membrane and therefore follows a novel biogenesis pathway

The GET pathway can increase the risk of mitochondrial outer membrane proteins to be mistargeted to the ER

Tail-anchored (TA) proteins are anchored to their corresponding membrane via a single transmembrane segment (TMS) at their C-terminus. In yeast, the targeting of TA proteins to the endoplasmic reticulum (ER) can be mediated by the guided entry of TA proteins (GET) pathway, whereas it is not yet clear how mitochondrial TA proteins are targeted to their destination. It is widely observed that some mitochondrial outer membrane (OM) proteins are mistargeted to the ER when overexpressed or when their targeting signal is masked. However, the mechanism of this erroneous sorting is currently unknown. In this study, we demonstrate the involvement of the GET machinery in mistargeting of non-optimal mitochondrial OM proteins to the ER. These findings suggest that the GET machinery can, in principle, recognize and guide mitochondrial and non-canonical TA proteins. Hence, under normal conditions, an active mitochondrial targeting pathway must exist that dominates the kinetic competition against other pathways

The GET pathway can increase the risk of mitochondrial outer membrane proteins to be mistargeted to the ER

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