Mitochondrial Calcium Regulates Rat Liver Regeneration Through the Modulation of Apoptosis

Subcellular Ca2+ signals control a variety of responses in the liver. For example, mitochondrial Ca2+ (Ca-mit(2+)) regulates apoptosis, whereas Ca2+ 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 Ca2+-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 Ca2+ 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;54:296-306)