A novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and development.
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.
Lu
Gang
G
Department of Anesthesiology, University of California at Los Angeles, Los Angeles, California 90095, USA.
Ren
Shuxun
S
Korge
Paavo
P
Choi
Jayoung
J
Dong
Yuan
Y
Weiss
James
J
Koehler
Carla
C
Chen
Jau-nian
JN
Wang
Yibin
Y
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002463:Cell Membrane Permeability; D002470:Cell Survival; D004625:Embryo, Nonmammalian / Q000201:enzymology / Q000378:metabolism; D006321:Heart / Q000196:embryology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071636:Protein Phosphatase 2C; D016415:Sequence Alignment; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000607456:PPM1A protein, human; C000607457:PPM1B protein, human; C000607460:PPM1G protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C