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LIVER AND BILIARY TRACT

Novel role of phospholipase C-1: regulation of liver mitochondrial Ca²⁺ uptake

Departments of ¹Surgery and ²Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-4753

Submitted 29 January 2004 ; accepted in final form 20 April 2004

Mitochondrial Ca²⁺ (mCa²⁺) handling is an important regulator of liver cell function that controls events ranging from cellular respiration and signal transduction to apoptosis. Cytosolic Ca²⁺ enters mitochondria through the ruthenium red-sensitive mCa²⁺ uniporter, but the mechanisms governing uniporter activity are unknown. Activation of many Ca²⁺ channels in the cell membrane requires PLC. This activation commonly occurs through phosphitidylinositol-4,5-biphosphate (PIP₂) hydrolysis and the production of the second messengers inositol 1,4,5-trisphosphate [I(1,4,5)P₃] and 1,2-diacylglycerol (DAG). PIP₂ was recently identified in mitochondria. We hypothesized that PLC exists in liver mitochondria and regulates mCa²⁺ uptake through the uniporter. Western blot analysis with anti-PLC antibodies demonstrated the presence of PLC-1 in pure preparations of mitochondrial membranes isolated from rat liver. In addition, the selective PLC inhibitor U-73122 dose-dependently blocked mCa²⁺ uptake when whole mitochondria were incubated at 37°C with ⁴⁵Ca²⁺. Increasing extra mCa²⁺ concentration significantly stimulated mCa²⁺ uptake, and U-73122 inhibited this effect. Spermine, a uniporter agonist, significantly increased mCa²⁺ uptake, whereas U-73122 dose-dependently blocked this effect. The inactive analog of U-73122, U-73343, did not affect mCa²⁺ uptake in any experimental condition. Membrane-permeable I(1,4,5)P₃ receptor antagonists 2-aminoethoxydiphenylborate and xestospongin C also inhibited mCa²⁺ uptake. Although extra mitochondrial I(1,4,5)P₃ had no effect on mCa²⁺ uptake, membrane-permeable DAG analogs 1-oleoyl-2-acetyl-sn-glycerol and DAG-lactone, which inhibit PLC activity, dose-dependently inhibited mCa²⁺ uptake. These data indicate that PLC-1 exists in liver mitochondria and is involved in regulating mCa²⁺ uptake through the uniporter.

calcium; uniporter; inositol trisphosphate; cat; 2-APB

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