A novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and development

  1. Gang Lu1,4,
  2. Shuxun Ren1,4,
  3. Paavo Korge3,
  4. Jayoung Choi5,
  5. Yuan Dong5,
  6. James Weiss2,3,
  7. Carla Koehler4,6,
  8. Jau-nian Chen4,5, and
  9. Yibin Wang1,2,3,4,7
  1. 1 Department of Anesthesiology, University of California at Los Angeles, Los Angeles, California 90095, USA;
  2. 2 Department of Physiology, University of California at Los Angeles, Los Angeles, California 90095, USA;
  3. 3 Department of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA;
  4. 4 Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA;
  5. 5 Department of Molecular, Cellular, and Developmental Biology, University of California at Los Angeles, Los Angeles, California 90095, USA;
  6. 6 Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90095, USA

Abstract

Mitochondria play a central role in the regulation of programmed cell death signaling. Here, we report the finding of a mitochondrial matrix-targeted protein phosphatase 2C family member (PP2Cm) that regulates mitochondrial membrane permeability transition pore (MPTP) opening and is essential for cell survival, embryonic development, and cardiac function. PP2Cm is highly conserved among vertebrates, with the highest expression levels detected in the heart and brain. Small hairpin RNA (shRNA)-mediated knockdown of PP2Cm resulted in cell death associated with loss of mitochondrial membrane potential in cultured cardiac mycoytes and an induction of hepatocyte apoptosis in vivo. PP2Cm-deficient mitochondria showed elevated susceptibility to calcium-induced MPTP opening, whereas mitochondrial oxidative phosphorylation activities were not affected. Finally, inactivation of PP2Cm in developing zebrafish embryos caused abnormal cardiac and neural development as well as heart failure associated with induced apoptosis. These data suggest that PP2Cm is a novel mitochondrial protein phosphatase that has a critical function in cell death and survival, and may play a role in regulating the MPTP opening.

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