title: LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins.
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 (UPR(mt)). 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 UPR(mt). 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 UPR(mt), this pathway may preferentially act to promote chaperone mediated refolding of proteins.
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia.
authors.forename: Ayenachew
authors.initials: A
authors.lastname: Bezawork-Geleta
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Brodie
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Dougan
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia.
authors.forename: Kaye N
authors.initials: KN
authors.lastname: Truscott
mesh_terms: D000818:Animals; D049071:Endopeptidase Clp / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D049070:Protease La / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D059748:Proteolysis; D051381:Rats; D056811:Unfolded Protein Response
chemical_list: D024101:Mitochondrial Proteins; D066329:Protein Aggregates; D049070:Protease La; D049071:Endopeptidase Clp; C528384:CLPX protein, human