Abstract
Maintenance of mitochondrial protein homeostasis is critical for proper cellular function. Under normal conditions resident molecular chaperones and proteases maintain protein homeostasis within the organelle. Under conditions of stress however, misfolded proteins accumulate leading to the activation of the mitochondrial unfolded protein response (UPRmt). While molecular chaperone assisted refolding of proteins in mammalian mitochondria has been well documented, the contribution of AAA+ proteases to the maintenance of protein homeostasis in this organelle remains unclear. To address this gap in knowledge we examined the contribution of human mitochondrial matrix proteases, LONM and CLPXP, to the turnover of OTC-∆, a folding incompetent mutant of ornithine transcarbamylase, known to activate UPRmt. Contrary to a model whereby CLPXP is believed to degrade misfolded proteins, we found that LONM, and not CLPXP is responsible for the turnover of OTC-∆ in human mitochondria. To analyse the conformational state of proteins that are recognised by LONM, we examined the turnover of unfolded and aggregated forms of malate dehydrogenase (MDH) and OTC. This analysis revealed that LONM specifically recognises and degrades unfolded, but not aggregated proteins. Since LONM is not upregulated by UPRmt, this pathway may preferentially act to promote chaperone mediated refolding of proteins.
Highlights
Proteins, organisms have evolved a number of integrated stress response pathways such as the heat shock response, envelope stress response and unfolded protein response in the ER3,10–12
Given that human mitochondrial CLPXP is known to recognise and degrade the model unfolded protein, casein and mammalian CLPP is transcriptionally upregulated upon over-expression of ornithine transcarbamylase (OTC)-Δ 25,36,37, it is reasonable to suggest that human CLPXP may play an important role in the degradation of misfolded proteins and subsequent stress signalling as reported in C. elegans
Maintenance of mitochondrial protein homeostasis and bioenergetics is fundamental to health and normal aging of eukaryotic organisms[14]
Summary
Proteins, organisms have evolved a number of integrated stress response pathways such as the heat shock response, envelope stress response and unfolded protein response in the ER3,10–12. This disturbance to protein homeostasis within the mitochondrion is sensed, and a mitochondria-to-nucleus signalling pathway is activated This pathway, known as the mitochondrial unfolded protein response (UPRmt), was initially identified in a monkey cell line, by over-expression of a folding-incompetent form of the mitochondrial protein, ornithine transcarbamylase (OTC) termed OTC-Δ 25. The redistribution of ATFS-1 to the nucleus is dependent on the inner membrane embedded ABC-family peptide transporter Haf-1 (Haf transporter 1) Both ClpX and ClpP from C. elegans have been experimentally implicated as direct components of the UPRmt signal transduction pathway[30,31]. UPRmt stress signalling by the direct and promiscuous degradation of unfolded proteins by CLPXP may not be a conserved mechanism
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