title: Mitochondrial calcium regulates rat liver regeneration through the modulation of apoptosis.
abstract: Subcellular Ca(2+) signals control a variety of responses in the liver. For example, mitochondrial Ca(2+) (Ca(mit)(2+)) regulates apoptosis, whereas Ca(2+) in the nucleus regulates cell proliferation. Because apoptosis and cell growth can be related, we investigated whether Ca(mit)(2+) also affects liver regeneration. The Ca(2+)-buffering protein parvalbumin, which was targeted to the mitochondrial matrix and fused to green fluorescent protein, was expressed in the SKHep1 liver cell line; the vector was called parvalbumin-mitochondrial targeting sequence-green fluorescent protein (PV-MITO-GFP). This construct properly localized to and effectively buffered Ca(2+) signals in the mitochondrial matrix. Additionally, the expression of PV-MITO-GFP reduced apoptosis induced by both intrinsic and extrinsic pathways. The reduction in cell death correlated with the increased expression of antiapoptotic genes [B cell lymphoma 2 (bcl-2), myeloid cell leukemia 1, and B cell lymphoma extra large] and with the decreased expression of proapoptotic genes [p53, B cell lymphoma 2-associated X protein (bax), apoptotic peptidase activating factor 1, and caspase-6]. PV-MITO-GFP was also expressed in hepatocytes in vivo with an adenoviral delivery system. Ca(mit)(2+) buffering in hepatocytes accelerated liver regeneration after partial hepatectomy, and this effect was associated with the increased expression of bcl-2 and the decreased expression of bax.
  
  
  CONCLUSIONS
  Together, these results reveal an essential role for Ca(mit)(2+) in hepatocyte proliferation and liver regeneration, which may be mediated by the regulation of apoptosis.
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Mateus T
authors.initials: MT
authors.lastname: Guerra
authors.forename: Emerson A
authors.initials: EA
authors.lastname: Fonseca
authors.forename: Flavia M
authors.initials: FM
authors.lastname: Melo
authors.forename: Viviane A
authors.initials: VA
authors.lastname: Andrade
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Aguiar
authors.forename: Lídia M
authors.initials: LM
authors.lastname: Andrade
authors.forename: Ana Cristina N
authors.initials: AC
authors.lastname: Pinheiro
authors.forename: Marisa C F
authors.initials: MC
authors.lastname: Casteluber
authors.forename: Rodrigo R
authors.initials: RR
authors.lastname: Resende
authors.forename: Mauro C X
authors.initials: MC
authors.lastname: Pinto
authors.forename: Simone O A
authors.initials: SO
authors.lastname: Fernandes
authors.forename: Valbert N
authors.initials: VN
authors.lastname: Cardoso
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Souza-Fagundes
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Menezes
authors.forename: Ana M
authors.initials: AM
authors.lastname: de Paula
authors.forename: Michael H
authors.initials: MH
authors.lastname: Nathanson
authors.forename: Maria de Fátima
authors.initials: Mde F
authors.lastname: Leite
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D049109:Cell Proliferation; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D023421:Models, Animal; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D002118:Calcium