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Mitochondrial calcium regulates rat liver regeneration through the modulation of apoptosis
Author(s) -
Guerra Mateus T.,
Fonseca Emerson A.,
Melo Flavia M.,
Andrade Viviane A.,
Aguiar Carla J.,
Andrade Lídia M.,
Pinheiro Ana Cristi.,
Casteluber Marisa C. F.,
Resende Rodrigo R.,
Pinto Mauro C. X.,
Fernandes Simone O. A.,
Cardoso Valbert N.,
SouzaFagundes Elaine M.,
Menezes Gustavo B.,
de Paula Ana M.,
Nathanson Michael H.,
de Fátima Leite Maria
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24367
Subject(s) - microbiology and biotechnology , apoptosis , biology , liver regeneration , mitochondrion , programmed cell death , cell growth , green fluorescent protein , regeneration (biology) , biochemistry , gene
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 . Conclusion: 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. (HEPATOLOGY 2011;)