title: Altered mitochondrial morphology and defective protein import reveal novel roles for Bax and/or Bak in skeletal muscle.
abstract: The function Bax and/or Bak in constituting a gateway for mitochondrial apoptosis in response to apoptotic stimuli has been unequivocally demonstrated. However, recent work has suggested that Bax/Bak may have unrecognized nonapoptotic functions related to mitochondrial function in nonstressful environments. Wild-type (WT) and Bax/Bak double knockout (DKO) mice were used to determine alternative roles for Bax and Bak in mitochondrial morphology and protein import in skeletal muscle. The absence of Bax and/or Bak altered mitochondrial dynamics by regulating protein components of the organelle fission and fusion machinery. Moreover, DKO mice exhibited defective mitochondrial protein import, both into the matrix and outer membrane compartments, which was consistent with our observations of impaired membrane potential and attenuated expression of protein import machinery (PIM) components in intermyofibrillar mitochondria. Furthermore, the cytosolic chaperones heat-shock protein 90 (Hsp90) and binding immunoglobulin protein (BiP) were markedly increased with the deletion of Bax/Bak, indicating that the cytosolic environment related to protein folding may be changed in DKO mice. Interestingly, endurance training fully restored the deficiency of protein import in DKO mice, likely via the upregulation of PIM components and through improved cytosolic chaperone protein expression. Thus our results emphasize novel roles for Bax and/or Bak in mitochondrial function and provide evidence, for the first time, of a curative function of exercise training in ameliorating a condition of defective mitochondrial protein import.
authors.affiliation: School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sobia
authors.initials: S
authors.lastname: Iqbal
authors.forename: Michael F N
authors.initials: MF
authors.lastname: O'Leary
authors.forename: Keir J
authors.initials: KJ
authors.lastname: Menzies
authors.forename: Ayesha
authors.initials: A
authors.lastname: Saleem
authors.forename: Shuzhe
authors.initials: S
authors.lastname: Ding
authors.forename: David A
authors.initials: DA
authors.lastname: Hood
mesh_terms: D000818:Animals; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D010805:Physical Conditioning, Animal; D010807:Physical Endurance / Q000235:genetics; D017510:Protein Folding; D021381:Protein Transport; D015398:Signal Transduction; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
keywords: apoptosis; exercise; gene expression; mitochondrial biogenesis; unfolded protein response