Unfolded activate apoptosis (Malhotra and Kaufman, 2011) In mitochondria,

Unfolded protein response (UPR) is an intercellular signalling pathway that accumulates of misfolded proteins in the ER lumen. Mitochondria and the endoplasmic reticulum work together to form a structural and functional network, that is essential to maintain a cellular homeostasis and to determine the cell fate under different pathophysiological conditions. To maintain control of pro-survival pathway, regulated Ca2+ from the endoplasmic reticulum to the mitochondria (Malhotra & Kaufman, 2011).

The purpose of the ER UPR is to control the response to the accumulated of unfolded or misfolded proteins in the lumen. There are three aims, first is to initially restore the normal function of the cell by slowing translation, activating the signalling pathway which leads to increasing the production of the molecular chaperones that are involved in the protein folding, and degrading the misfolded proteins. If these objectives are not achieved within a certain span or the disruption is prolonged, the UPR will activate apoptosis (Malhotra and Kaufman, 2011)

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In mitochondria, mitochondrial unfolded protein response (UPRmt) is a cellular stress response (Zhao, Wang, et al, 2002). Apoptosis does not occur in the UPRmt because the protease is managed to clean up the aggregates. All the proteins within the mitochondria start to degrade during UPRmt as it is beyond the capacity for the chaperone proteins to handle them, this results in the mitochondria to become less functional. The UPRmt can happen in the mitochondrial matrix or the inner membrane (Pellegrino, Nargund and Haynes, 2013).

I.                Discuss the similarities and differences between the UPR in the endoplasmic reticulum and the UPR in the mitochondria.

Mitochondria’s classical concept the powerhouse of the cells and an isolated organelle has been challenged over time with the realization that the mitochondria function continually remodels by both fusion and fission events. Both the organelles ER and mitochondria are both dynamic and capable of modifying the structure and function in response to the environmental conditions. They both interact functionally and physically with each other, and one of the important aspects of this interaction is calcium signalling between the two organelles (shown in figure 1). The ER and mitochondria have a 20% close contact in between (Kornmann et al. 2009), this contact which the ER connects with the mitochondria are referred to as (MAM) mitochondrial associated membrane (Vance 1990). This interaction has pivotal roles in numerous cellular function with lipid transport, calcium signalling, energy metabolism and the cell survival (Stone and Vance 2000).

The endoplasmic reticulum and mitochondria are both exposed to nascent polypeptides, both need dedicated protein-folding machinery, constituting each organelle’s protein folding capacity (Pellegrino, Nargund and Haynes, 2013). There are different signalling mechanisms for ER and mitochondria due to the different shapes of the organelle. The ER-localized membrane spanning Kinase (lre1) in the luminal domain, directly senses the unfolded proteins and transmits the signal information to the cytosolic domain of lre1. The signal directly activates the transcription factor Xbp1 (Walter & Ron, 2011). The mitochondria have a different stress responses that respond to perturbations in the matrix. The current shape of the UPRmt signalling suggests that the unfolded or misfolded proteins are being detected in the matrix by ClpP a quality control, which degrades the proteins into peptides. The peptides are then transported into the inner membrane, this leads the activation of ATFS-1 through an unknown mechanism (Pellegrino, Nargund and Haynes, 2013).