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Mechanisms regulating cytochrome c release in pancreatic mitochondria
  1. Irina V Odinokova (odinokova{at}rambler.ru)
  1. VA Greater Los Angeles Healthcare System and UCLA; 2Institute of Theoretical and Experimental Bioph, United States
    1. Kai-Feng Sung (skftyh{at}yahoo.com.tw)
    1. VA Greater Los Angeles Healthcare System and UCLA; 3Chang Gung Memorial Hospital, Taipei, Taiwa, United States
      1. Olga A Mareninova (olgam{at}ucla.edu)
      1. VA Greater Los Angeles Healthcare System and UCLA, United States
        1. Kip Hermann (waserbal{at}ucla.edu)
        1. VA Greater Los Angeles Healthcare System and UCLA, United States
          1. Yuri Evtodienko (evtodienko{at}msn.com)
          1. Institute of Theoretical and Experimental Biophysics, Academy of Sciences, Moscow Region, Russian Federation
            1. Alexander Andreyev (andreyev{at}ucsd.edu)
            1. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, United States
              1. Ilya Gukovsky (igukovsk{at}ucla.edu)
              1. VA Greater Los Angeles Healthcare System and UCLA, United States
                1. Anna S Gukovskaya (agukovsk{at}ucla.edu)
                1. VA Greater Los Angeles Healthcare System and UCLA, United States

                  Abstract

                  Mechanisms of acinar cell death in pancreatitis are poorly understood. Cytochrome c release is a central event in apoptosis in pancreatitis. Here, we assessed the regulation of pancreatic cytochrome c release by Ca2+, mitochondrial membrane potential (ΔΨm), and reactive oxygen species (ROS), the signals involved in acute pancreatitis. We used both isolated rat pancreatic mitochondria and intact acinar cells hyperstimulated with CCK-8 (in vitro model of acute pancreatitis). Micromolar Ca2+ depolarized isolated pancreatic mitochondria through a mechanism different from the ″classical″ (i.e., liver) permeability transition pore (mPTP). In contrast with liver, Ca2+-induced mPTP opening caused a dramatic decrease in ROS and was not associated with pancreatic mitochondria swelling. Importantly, we found that Ca2+-induced depolarization inhibited cytochrome c release from pancreatic mitochondria, due to blockade of ROS production. As a result, Ca2+ exerted two opposite effects on cytochrome c release: Ca2+ per se stimulated whereas Ca2+-induced depolarization inhibited it. This dual effect caused a non-monotonous dose-dependence of cytochrome c release on Ca2+. In intact acinar cells, cytochrome c release, caspase activation and apoptosis were all stimulated by ROS and Ca2+ and inhibited by depolarization, corroborating the findings on isolated pancreatic mitochondria. These data implicate ROS as a key mediator of CCK-induced apoptotic responses. The results indicate a major role for mitochondria in the effects of Ca2+ and ROS on acinar cell death. They suggest that the extent of apoptosis in pancreatitis is regulated by the interplay between ROS, ΔΨm and Ca2+. Stabilizing mitochondria against loss of ΔΨm may represent a strategy to mitigate the severity of pancreatitis.

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