title: Ablation of the mitochondrial complex IV assembly protein Surf1 leads to increased expression of the UPR(MT) and increased resistance to oxidative stress in primary cultures of fibroblasts.
abstract: Mice deficient in the electron transport chain (ETC) complex IV assembly protein SURF1 have reduced assembly and activity of cytochrome c oxidase that is associated with an upregulation of components of the mitochondrial unfolded protein response (UPR(MT)) and increased mitochondrial number. We hypothesized that the upregulation of proteins associated with the UPR(MT) in response to reduced cytochrome c oxidase activity in Surf1(-/-) mice might contribute to increased stress resistance. To test this hypothesis we asked whether primary cultures of fibroblasts from Surf1(-/-) mice exhibit enhanced resistance to stressors compared to wild-type fibroblasts. Here we show that primary dermal fibroblasts isolated from Surf1(-/-) mice have increased expression of UPR(MT) components ClpP and Hsp60, and increased expression of Lon protease. Fibroblasts from Surf1(-/-) mice are significantly more resistant to cell death caused by oxidative stress induced by paraquat or tert-Butyl hydroperoxide compared to cells from wild-type mice. In contrast, Surf1(-/-) fibroblasts show no difference in sensitivity to hydrogen peroxide stress. The enhanced cell survival in response to paraquat or tert-Butyl hydroperoxide in Surf1(-/-) fibroblasts compared to wild-type fibroblasts is associated with induced expression of Lon, ClpP, and Hsp60, increased maximal respiration, and increased reserve capacity as measured using the Seahorse Extracellular Flux Analyzer. Overall these data support a protective role for the activation of the UPR(MT) in cell survival.
authors.affiliation: Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK 73104, United States; Department of Physiology, Oklahoma University Health Science Center, 940 S.L. Young Blvd, Oklahoma City, OK 73104, United States.
authors.forename: Gavin
authors.initials: G
authors.lastname: Pharaoh
authors.affiliation: Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK 73104, United States; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pulliam
authors.affiliation: Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK 73104, United States; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, United States.
authors.forename: Shauna
authors.initials: S
authors.lastname: Hill
authors.affiliation: Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK 73104, United States.
authors.forename: Kavithalakshmi
authors.initials: K
authors.lastname: Sataranatarajan
authors.affiliation: Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK 73104, United States; Oklahoma City VA Medical Center, 921 NE 13th St, Oklahoma City, OK 73104, United States; Department of Physiology, Oklahoma University Health Science Center, 940 S.L. Young Blvd, Oklahoma City, OK 73104, United States. Electronic address: Holly-VanRemmen@omrf.org.
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
mesh_terms: D000818:Animals; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000633:toxicity; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C092928:Surf-1 protein; D006861:Hydrogen Peroxide; D003576:Electron Transport Complex IV
keywords: Hydrogen peroxide (H(2)O(2)); Mitochondrial unfolded protein response (UPR(MT)); Paraquat (PQ); Primary mouse fibroblasts; Stress resistance; Tert-butyl hydroperoxide (t-BuOOH)