title: Mitochondrial enzymes are protected from stress-induced aggregation by mitochondrial chaperones and the Pim1/LON protease.
abstract: Proteins in a natural environment are constantly challenged by stress conditions, causing their destabilization, unfolding, and, ultimately, aggregation. Protein aggregation has been associated with a wide variety of pathological conditions, especially neurodegenerative disorders, stressing the importance of adequate cellular protein quality control measures to counteract aggregate formation. To secure protein homeostasis, mitochondria contain an elaborate protein quality control system, consisting of chaperones and ATP-dependent proteases. To determine the effects of protein aggregation on the functional integrity of mitochondria, we set out to identify aggregation-prone endogenous mitochondrial proteins. We could show that major metabolic pathways in mitochondria were affected by the aggregation of key enzyme components, which were largely inactivated after heat stress. Furthermore, treatment with elevated levels of reactive oxygen species strongly influenced the aggregation behavior, in particular in combination with elevated temperatures. Using specific chaperone mutant strains, we showed a protective effect of the mitochondrial Hsp70 and Hsp60 chaperone systems. Moreover, accumulation of aggregated polypeptides was strongly decreased by the AAA-protease Pim1/LON. We therefore propose that the proteolytic breakdown of aggregation-prone polypeptides represents a major protective strategy to prevent the in vivo formation of aggregates in mitochondria.
authors.affiliation: Institut für Biochemie und Molekularbiologie (IBMB), Universität Bonn, Nussallee 11, D-53115 Bonn, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Bender
authors.forename: Ilka
authors.initials: I
authors.lastname: Lewrenz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Franken
authors.forename: Catherina
authors.initials: C
authors.lastname: Baitzel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Voos
mesh_terms: D049069:ATP-Dependent Proteases / Q000378:metabolism*; D018834:Chaperonin 60 / Q000378:metabolism; D004789:Enzyme Activation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D018384:Oxidative Stress; D020836:Protein Structure, Quaternary; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D018834:Chaperonin 60; C504495:HSP60 protein, S cerevisiae; D018840:HSP70 Heat-Shock Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D049069:ATP-Dependent Proteases; C085155:PIM1 protein, S cerevisiae; D012697:Serine Endopeptidases