title: Bcl-xL overexpression blocks bax-mediated mitochondrial contact site formation and apoptosis in rod photoreceptors of lead-exposed mice.
abstract: Photoreceptor apoptosis and resultant visual deficits occur in humans and animals with inherited and disease-, injury-, and chemical-induced retinal degeneration. A clinically relevant mouse model of progressive rod photoreceptor-selective apoptosis was produced by low-level developmental lead exposure and studied in combination with transgenic mice overexpressing Bcl-x(L) only in the photoreceptors. A multiparametric analysis of rod apoptosis and mitochondrial structure-function was performed. Mitochondrial cristae topography and connectivity, matrix volume, and contact sites were examined by using 3D electron tomography. Lead-induced rod-selective apoptosis was accompanied by rod Ca(2+) overload, rhodopsin loss, translocation of Bax from the cytosol to the mitochondria, decreased rod mitochondrial respiration and membrane potential, mitochondrial cytochrome c release, caspase-3 activation, and an increase in the number of mitochondrial contact sites. These effects occurred without mitochondrial matrix swelling, outer membrane rupture, caspase-8 activation, or Bid cleavage. Bcl-x(L) overexpression completely blocked all apoptotic events, except Ca(2+) overload, and maintained normal rod mitochondrial function throughout adulthood. This study presents images of mitochondrial contact sites in an in vivo apoptosis model and shows that Bcl-x(L) overexpression blocks increased contact sites and apoptosis. These findings extend our in vitro retinal studies with Pb(2+) and Ca(2+) and suggest that developmental lead exposure produced rod-selective apoptosis without mitochondrial swelling by translocating cytosolic Bax to the mitochondria, which likely sensitized the Pb(2+) and Ca(2+) overloaded rod mitochondria to release cytochrome c. These results have relevance for therapies in a wide variety of progressive retinal and neuronal degenerations where Ca(2+) overload, lead exposure, andor mitochondrial dysfunction occur.
authors.affiliation: College of Optometry, Department of Biology, University of Houston, Houston, TX 77204, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: He
authors.forename: Guy A
authors.initials: GA
authors.lastname: Perkins
authors.forename: Ann T
authors.initials: AT
authors.lastname: Poblenz
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Harris
authors.forename: Michael
authors.initials: M
authors.lastname: Hung
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Donald A
authors.initials: DA
authors.lastname: Fox
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005260:Female; D007700:Kinetics; D007854:Lead / Q000009:adverse effects*; D007855:Lead Poisoning; D008291:Malate Dehydrogenase / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D010101:Oxygen Consumption; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012160:Retina / Q000378:metabolism; D012243:Rhodopsin / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D007854:Lead; D012243:Rhodopsin; D008291:Malate Dehydrogenase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D002118:Calcium