Role of cyclophilin D in the resistance of brain mitochondria to the permeability transition.
The mitochondrial permeability transition (MPT) is involved in both necrosis and apoptosis. Cyclophilin D (CypD) is an important component of the MPT. Brain mitochondria are more resistant to the MPT when compared to heart or liver mitochondria. We found that this increased resistance correlates with low expression of CypD in brain when compared to heart or liver. In newborn rats, sensitivity of brain mitochondria to the MPT and CypD expression are significantly higher than in mature animals. In an in vitro model of neuronal development, mitochondria in differentiated neuronal-like cells exert a higher calcium threshold toward MPT induction and express significantly less CypD when compared to undifferentiated precursor cells. Gain and loss of function experiments confirm the role of CypD in sensitivity to the MPT. Together our data indicate that the increased calcium threshold of brain mitochondria to the MPT correlates with low expression of CypD in brain; and that neuronal cells lose CypD during differentiation and become less sensitive to the MPT induction. This may be a protection mechanism that raises the threshold of brain tissue against injuries.
Eliseev
Roman A
RA
Musculoskeletal Research Center, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States. roman eliseev@urmc.rochester.edu
Filippov
Gleb
G
Velos
Janice
J
VanWinkle
Beth
B
Goldman
Aaron
A
Rosier
Randy N
RN
Gunter
Thomas E
TE
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000502:physiology*; D019610:Cytoprotection / Q000502:physiology*; D005260:Female; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D013234:Stem Cells / Q000378:metabolism
D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D021983:Cyclophilins; D002118:Calcium