Mitochondrial Lon regulates apoptosis through the association with Hsp60-mtHsp70 complex.

Human Lon protease is a mitochondrial matrix protein with several functions, including protein degradation, mitochondrial DNA (mtDNA) binding, and chaperone activity. Lon is currently emerging as an important regulator of mitochondria-contributed tumorigenesis due to its overexpression in cancer cells. To understand the mechanism of increased Lon in tumor cells, we studied the interactome to identify the chaperone Lon-associated proteins by proteomics approaches using the cells overexpressing Lon. In the present study, we designed a method connecting co-immunoprecipitation (Co-IP) to in-solution digestion for the shotgun mass spectrometry. We identified 76 proteins that were putative Lon-associated proteins that participated in mitochondrial chaperone system, cellular metabolism and energy, cell death and survival, and mtDNA stability. The association between Lon and NDUFS8 or Hsp60-mtHsp70 complex was confirmed by Co-IP and immunofluorescence co-localization assay. We then found that the protein stability/level of Hsp60-mtHsp70 complex depends on the level of Lon under oxidative stress. Most importantly, the ability of increased Lon-inhibited apoptosis is dependent on Hsp60 that binds p53 to inhibit apoptosis. These results suggest that the mechanism underlying cell survival regulated by Lon is mediated by the maintenance of the protein stability of Hsp60-mtHsp70 complex. This new knowledge of chaperone Lon interactome will allow us to better understand the cellular mechanism of Lon in mitochondrial function and of its overexpression in enhancing cell survival and tumorigenesis.

Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species.

Lon protease is a multifunction protein and operates in protein quality control and stress response pathways in mitochondria. Human Lon is upregulated under oxidative and hypoxic stresses that represent the stress phenotypes of cancer. However, little literature undertakes comprehensive and detailed investigations on the tumorigenic role of Lon. Overexpression of Lon promotes cell proliferation, apoptotic resistance to stresses, and transformation. Furthermore, Lon overexpression induces the production of mitochondrial reactive oxygen species (ROS) that result from Lon-mediated upregulation of NDUFS8, a mitochondrial Fe-S protein in complex I of electron transport chain. Increased level of mitochondrial ROS promotes cell proliferation, cell survival, cell migration, and epithelial-mesenchymal transition through mitogen-activated protein kinase (MAPK) and Ras-ERK activation. Overall, the present report for the first time demonstrates the role of Lon overexpression in tumorigenesis. Lon overexpression gives an apoptotic resistance to stresses and induces mitochondrial ROS production through Complex I as signaling molecules to activate Ras and MAPK signaling, giving the survival advantages and adaptation to cancer cells. Finally, in silico and immunohistochemistry analysis showed that Lon is overexpressed specifically in various types of cancer tissue including oral cancer.

Occupational contact urticaria: Australian data.

BACKGROUND: Over the last 30 years there has been increasing recognition of the clinical entity contact urticaria (CU) and the related diagnosis, protein contact dermatitis. However, there are relatively few reports of the occupational relevance of this condition. OBJECTIVES: To describe relevant characteristics of patients diagnosed with occupational CU (OCU) in a tertiary level specialist occupational dermatology clinic in Australia. METHODS: We performed a retrospective analysis of all patients diagnosed with OCU at an occupational dermatology clinic in Melbourne between 1 January 1993 and 31 December 2004. We identified 151 cases of CU diagnosed over the 12-year period. RESULTS: OCU was diagnosed in 8.3% (143 of 1720) of the total number of patients with occupational skin disease. Natural rubber latex accounted for the majority of all cases of OCU. Other common causes were foodstuffs and ammonium persulphate utilized as hairdressing bleach. The most commonly affected sites were the hands, followed by the arms and face. The most frequently affected occupations were healthcare workers, food handlers and hairdressers. All cases of CU in patients with hand symptoms were assessed to be work related. Atopy was a significant risk factor for both latex-related and nonlatex-related OCU. CONCLUSIONS: Radioallergosorbent tests and skin prick testing, including to patients' own food samples, should be part of the routine assessment of patients in high-risk occupations for OCU, particularly if the hands are affected, there is a history of atopy and there is exposure to urticants. We emphasize the importance of both determining the role of occupation in the causation of CU and recognizing all contributory factors in complex cases of occupational contact dermatitis of the hands.