In mammalian cells, the most well defined unfolded protein response (UPR) is mediated by proteins that span the endoplasmic reticulum membrane. This UPR prevents the accumulation of deleterious unfolded protein aggregates. However in eukaryotic cells mitochondria form another compartment with protein-folding function, and hence there also appears to be a specific mitochondrial UPR (UPR^mt). Studies carried out in C.elegans have shown that in response to mitochondrial protein misfolding CLPP-1 conveys a signal to the cytoplasm resulting in UBL-5 and DVE-1 forming a complex that can up-regulate the expression of mitochondrial chaperone genes. The Ubl-5 gene itself is also upregulated, which in turn acts to amplify the UPR^mt. UBL-5 therefore appears to have a key role in the response to mitochondrial stress. However the importance of UBL-5 in protecting mammalian cells exposed to stresses such as excess nutrient availability has not previously been investigated.
To determine whether excess nutrients can affect the UPR^mt we incubated C2C12 myotubes with either 20 mM glucose or 0.75 mM palmitate for 18 hrs and assessed the levels of Clpp and Ubl5 mRNA transcripts as well as cell viability. We found that both high glucose and palmitate significantly reduced cellular ATP levels, and that this was associated with increased Clpp expression indicative of ‘mitochondrial stress’. In the high glucose condition this mitochondrial stress signal was accompanied by an increase in Ubl5 expression, and under these circumstances there was no change in cell viability. In contrast the palmitate incubation did not lead to an increase in Ubl5 gene expression and this resulted in a significant decrease in cell viability.
Therefore it appears that when Ubl5 expression is increased in response to mitochondrial stress, muscle cells are protected against cell death, whereas a lack of a Ubl5 response is associated reduced cell viability.