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Fine‐tuning of hepatocyte calcium signaling and liver regeneration by the mitochondrial calcium uniporter
Author(s) -
Antony Anil Noronha,
Katona Máté,
Juskeviciute Egle,
Elrod John W.,
Hajnóczky György,
Hoek Jan B.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.536.10
Subject(s) - uniporter , microbiology and biotechnology , calcium signaling , mitochondrion , calcium , biology , cytosol , signal transduction , mitochondrial permeability transition pore , calcium pump , chemistry , programmed cell death , biochemistry , apoptosis , atpase , organic chemistry , enzyme
Calcium (Ca 2+ ) signaling regulates a variety of cellular processes such as metabolism, cell proliferation, division and differentiation, gene transcription, stimulus‐secretion coupling and cell death. Ca 2+ is able to regulate these diverse cellular processes due to the versatility of the Ca 2+ signaling mechanism in terms of speed, amplitude and spatiotemporal patterning. Mitochondria form an integral part of this machinery, both as regulators and targets of Ca 2+ signaling. In recent years, leading‐edge research in the field of mCa 2+ (mitochondrial Ca 2+ ) handling and its implications for cellular Ca 2+ homeostasis opened up the possibility to investigate the functional implications of mCa 2+ uptake in shaping the spatiotemporal dynamics of Ca 2+ signaling, and regulating cellular metabolism (through activation of Ca 2+ sensitive TCA cycle enzymes) and mitochondria‐mediated cell death (through mitochondrial permeability transition). mCa 2+ is mediated by the mitochondrial uniporter complex, consisting of the pore forming MCU (Mitochondrial Calcium Uniporter) and regulators such as MICU1 (mitochondrial calcium uptake 1), MICU2 and EMRE (essential MCU regulator). MCU deletion abolishes mCa 2+ uptake in mouse hepatocytes driven by vasopressin‐evoked cCa 2+ (cytosolic Ca 2+ ) increases. This lack of mCa 2+ uptake resulted in alterations in cCa 2+ dynamics, including an elevated resting [cCa 2+ ] and a reduced cCa 2+ peak and the total Ca 2+ mobilization in response to vasopressin stimulation. These changes in cCa 2+ dynamics could lead to alterations in downstream Ca 2+ responsive signaling events. Indeed, we see suppression of AMPK activation through CAMKK2, in response to hormone‐evoked Ca 2+ signals in MCU KD hepatocytes. Activation of Creb, CAMKK2, AMPKα and ERK1/2 are also more transient in the MCU KD hepatocytes compared to controls. Our previous studies have highlighted the importance of regulating MCU (through MICU1) under stress conditions involving enhanced mCa 2+ entry, especially during liver regeneration following partial hepatectomy (PHx). Enhanced mCa 2+ entry during liver regeneration maybe vital to cellular signaling events and increased mitochondrial ATP production. The lack of mCa 2+ uptake in hepatocyte‐specific MCU KD mice resulted in decelerated kinetics of cell cycle progression after PHx reflected by the inhibition in BrdU incorporation and Ki67 upregulation at 30h post‐PHx, which recovers by 36h. Interestingly, apart from an inhibition in Cyclin D1 expression, many cell cycle regulatory proteins remained unchanged in the KD compared to WT controls. Cell signaling events such as AMPK, CAMKK2 and mTOR activation post‐PHx are altered. Gene expression analysis at 30h post‐PHx revealed massive changes in gene expression profiles between KD and control livers, especially in genes involving metabolic processes and protein synthesis in response to PHx. Overall, the lack of mCa 2+ uptake affects multiple signaling and metabolic pathways in hepatocytes and impacts the kinetics of the liver regeneration response. Support or Funding Information AA018873 and U01EB023224 (JBH) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .