title: Mitochondria-localized caveolin in adaptation to cellular stress and injury.
abstract: We show here that the apposition of plasma membrane caveolae and mitochondria (first noted in electron micrographs >50 yr ago) and caveolae-mitochondria interaction regulates adaptation to cellular stress by modulating the structure and function of mitochondria. In C57Bl/6 mice engineered to overexpress caveolin specifically in cardiac myocytes (Cav-3 OE), localization of caveolin to mitochondria increases membrane rigidity (4.2%; P<0.05), tolerance to calcium, and respiratory function (72% increase in state 3 and 23% increase in complex IV activity; P<0.05), while reducing stress-induced generation of reactive oxygen species (by 20% in cellular superoxide and 41 and 28% in mitochondrial superoxide under states 4 and 3, respectively; P<0.05) in Cav-3 OE vs. TGneg. By contrast, mitochondrial function is abnormal in caveolin-knockout mice and Caenorhabditis elegans with null mutations in caveolin (60% increase free radical in Cav-2 C. elegans mutants; P<0.05). In human colon cancer cells, mitochondria with increased caveolin have a 30% decrease in apoptotic stress (P<0.05), but cells with disrupted mitochondria-caveolin interaction have a 30% increase in stress response (P<0.05). Targeted gene transfer of caveolin to mitochondria in C57Bl/6 mice increases cardiac mitochondria tolerance to calcium, enhances respiratory function (increases of 90% state 4, 220% state 3, 88% complex IV activity; P<0.05), and decreases (by 33%) cardiac damage (P<0.05). Physical association and apparently the transfer of caveolin between caveolae and mitochondria is thus a conserved cellular response that confers protection from cellular damage in a variety of tissues and settings.
authors.affiliation: Department of Anesthesiology, University of California-San Diego, La Jolla, California 92161, USA.
authors.forename: Heidi N
authors.initials: HN
authors.lastname: Fridolfsson
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kawaraguchi
authors.forename: Sameh S
authors.initials: SS
authors.lastname: Ali
authors.forename: Mathivadhani
authors.initials: M
authors.lastname: Panneerselvam
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Niesman
authors.forename: J Cameron
authors.initials: JC
authors.lastname: Finley
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kellerhals
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Migita
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.forename: Ana L
authors.initials: AL
authors.lastname: Moreno
authors.forename: Michelle
authors.initials: M
authors.lastname: Jennings
authors.forename: Michael W
authors.initials: MW
authors.lastname: Kidd
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Bonds
authors.forename: Ravi C
authors.initials: RC
authors.lastname: Balijepalli
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ross
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyanohara
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lesnefsky
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.forename: Paul A
authors.initials: PA
authors.lastname: Insel
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000633:toxicity; D022461:Caveolins / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000032:analysis; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D022461:Caveolins; D017382:Reactive Oxygen Species; D002118:Calcium