Mitochondrial calcium regulates rat liver regeneration through the modulation of apoptosis

Abstract

Subcellular Ca2+ signals control a variety of responses in the liver. For example, mitochondrial Ca2+ regulates apoptosis while Ca2+ in the nucleus regulates cell proliferation. Since apoptosis and cell growth can be related, we investigated whether mitochondrial Ca2+ also affects liver regeneration. The Ca2+ buffering protein, Parvalbumin (PV), targeted to the mitochondrial matrix and fused to green fluorescent protein (PV-MITO-GFP) was expressed in the SKHep1 liver cell line. This construct properly localized to and effectively buffered Ca2+ signals in the mitochondrial matrix. Additionally, expression of PV-MITO-GFP reduced apoptosis induced by both the intrinsic and extrinsic pathways. The reduction in cell death correlated with increased expression of anti-apoptotic genes bcl-2, mcl-1, and bcl-xL, and decreased expression of the pro-apoptotic genes p53, bax, apaf-1 and caspase-6. PV-MITO-GFP was also expressed in hepatocytes in vivo using an adenoviral delivery system. Buffering mitochondrial Ca2+ in hepatocytes accelerated liver regeneration after partial hepatectomy, an effect that was associated with increased expression of Bcl-2 and decreased expression of Bax. Conclusion Together, these results reveal an essential role for mitochondrial Ca2+ in hepatocyte proliferation and liver regeneration, which may be mediated by regulating apoptosis.

Calcium signaling and cell proliferation

“…A C C E P T E D M A N U S C R I P T Ca 2+ channels and intracellular Ca 2+ stores are known to regulate proliferation and phenotype determination in differentiation processes [12,13,[69][70][71][72][73][74][75][76]. Deletion assays of STIM2 in B-cells impairs NFAT-dependent IL-10 production with only a modest reduction in store-operated Ca 2+ influx [77].…”

Calcium Signaling in the Liver

“…A recent report has shown that [Ca 2+ ]m signals also play an important role in the progression of liver regeneration after PH (145). Experiments in SkHep1 cells expressing PV in the mitochondria revealed that buffering of [Ca 2+ ]m leads to decreased apoptosis through altered expression of proapoptotic and antiapoptotic proteins.…”

Type 2 inositol trisphosphate receptor gene expression in hepatocytes is regulated by cyclic AMP

“…The type 2 isoform (IP3R2) is perhaps the least studied of the three [4]. It is the principal isoform in hepatocytes [5], and so may be important for calcium-mediated functions such as metabolism [6, 7], bile secretion [8, 9], and liver regeneration [10, 11]. Several factors phosphorylate this isoform of the receptor to modulate its calcium-release properties, including PKA [12], CaMK-II [13], and mTOR [14].…”