title: The Mitochondrial Lon Protease Is Required for Age-Specific and Sex-Specific Adaptation to Oxidative Stress.
abstract: Multiple human diseases involving chronic oxidative stress show a significant sex bias, including neurodegenerative diseases, cancer, immune dysfunction, diabetes, and cardiovascular disease. However, a possible molecular mechanism for the sex bias in physiological adaptation to oxidative stress remains unclear. Here, we report that Drosophila melanogaster females but not males adapt to hydrogen peroxide stress, whereas males but not females adapt to paraquat (superoxide) stress. Stress adaptation in each sex requires the conserved mitochondrial Lon protease and is associated with sex-specific expression of Lon protein isoforms and proteolytic activity. Adaptation to oxidative stress is lost with age in both sexes. Transgenic expression of transformer gene during development transforms chromosomal males into pseudo-females and confers the female-specific pattern of Lon isoform expression, Lon proteolytic activity induction, and H2O2stress adaptation; these effects were also observed using adult-specific transformation. Conversely, knockdown of transformer in chromosomal females eliminates the female-specific Lon isoform expression, Lon proteolytic activity induction, and H2O2stress adaptation and produces the male-specific paraquat (superoxide) stress adaptation. Sex-specific expression of alternative Lon isoforms was also observed in mouse tissues. The results develop Drosophila melanogaster as a model for sex-specific stress adaptation regulated by the Lon protease, with potential implications for understanding sexual dimorphism in human disease.
authors.affiliation: Ethel Percy Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Laura C D
authors.initials: LCD
authors.lastname: Pomatto
authors.affiliation: Ethel Percy Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Carney
authors.affiliation: Ethel Percy Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Shen
authors.affiliation: Ethel Percy Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wong
authors.affiliation: Ethel Percy Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Halaszynski
authors.affiliation: Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Salomon
authors.affiliation: Ethel Percy Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Kelvin J A
authors.initials: KJA
authors.lastname: Davies
authors.affiliation: Ethel Percy Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: jtower@usc.edu.
authors.forename: John
authors.initials: J
authors.lastname: Tower
mesh_terms: D000222:Adaptation, Physiological; D000367:Age Factors; D000818:Animals; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006540:Herbicides / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology; D049070:Protease La / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D006540:Herbicides; D016877:Oxidants; D006861:Hydrogen Peroxide; D049070:Protease La; D010269:Paraquat
keywords: Lon; adaptation; aging; hormesis; hydrogen peroxide; mitochondria; oxidative stress; paraquat; sexual differentiation; transformer