Cyclophilin D-sensitive mitochondrial permeability transition in adult human brain and liver mitochondria.
The mitochondrial permeability transition (mPT) is considered to be a major cause of cell death under a variety of pathophysiological conditions of the central nervous system (CNS) and other organs. Pharmacological inhibition or genetic knockout of the matrix protein cyclophilin D (CypD) prevents mPT and cell degeneration in several models of brain injury. If these findings in animal models are translatable to human disease, pharmacological inhibition of mPT offers a promising therapeutic target. The objective of this study was to validate the presence of a CypD-sensitive mPT in adult human brain and liver mitochondria. In order to perform functional characterization of human mitochondria, fresh tissue samples were obtained during hemorrhage or tumor surgery and mitochondria were rapidly isolated. Mitochondrial calcium retention capacity, a quantitative assay for mPT, was significantly increased by the CypD inhibitor cyclosporin A in both human brain and liver mitochondria, whereas thiol-reactive compounds and oxidants sensitized mitochondria to calcium-induced mPT. Brain mitochondria underwent swelling upon calcium overload, which was reversible upon calcium removal. To further explore mPT of human mitochondria, liver mitochondria were demonstrated to exhibit several classical features of the mPT phenomenon, such as calcium-induced loss of membrane potential and respiratory coupling, as well as release of the pro-apoptotic protein cytochrome c. We concluded that adult viable human brain and liver mitochondria possess an active CypD-sensitive mPT. Our findings support the rationale of CypD and mPT inhibition as pharmacological targets in acute and chronic neurodegeneration.
Mitochondrial Pathophysiology Unit, Laboratory for Experimental Brain Research, Department of Clinical Sciences, Lund University, Lund, Sweden. magnus.hansson@med.lu.se
Magnus J
MJ
Hansson
Saori
S
Morota
Li
L
Chen
Nagahisa
N
Matsuyama
Yoshiaki
Y
Suzuki
Satoshi
S
Nakajima
Tadashi
T
Tanoue
Akibumi
A
Omi
Futoshi
F
Shibasaki
Motohide
M
Shimazu
Yukio
Y
Ikeda
Hiroyuki
H
Uchino
Eskil
E
Elmér
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure*; D019069:Cell Respiration / Q000502:physiology; D021983:Cyclophilins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000648:ultrastructure; D010539:Permeability; D000097322:Peptidyl-Prolyl Isomerase D
D021983:Cyclophilins; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D