Aromatase deficiency inhibits the permeability transition in mouse liver mitochondria.
Lack of estrogens affects male physiology in a number of ways, including severe changes in liver metabolism that result in lipid accumulation and massive hepatic steatosis. Here we investigated whether estrogen deficiency may alter the functionality and permeability properties of liver mitochondria using, as an experimental model, aromatase knockout (ArKO) male mice, which cannot synthesize endogenous estrogens due to a disruption of the Cyp19 gene. Liver mitochondria isolated from ArKO mice displayed increased activity of the mitochondrial respiratory complex IV compared with wild-type mice and were less prone to undergo cyclosporin A-sensitive mitochondrial permeability transition (MPT) induced by calcium loading. The altered permeability properties of the mitochondrial membranes were not due to changes in reactive oxygen species, ATP levels, or mitochondrial membrane potential but were associated with increased content of the phospholipid cardiolipin, structural component of the mitochondrial membranes and regulator of the MPT pore, and with increased mitochondrial protein levels of Bcl-2 and the adenine nucleotide translocator (ANT), regulator and component of the MPT pore, respectively. Real-time RT-PCR demonstrated increased mRNA levels for Bcl-2 and ANT2 but not for the ANT1 isoform in ArKO livers. Supplementation of 17beta-estradiol retrieved ArKO mice from massive hepatic steatosis and restored mitochondrial permeability properties, cardiolipin, Bcl-2, and ANT2 levels. Overall, our findings demonstrate an important role of estrogens in the modulation of hepatic mitochondrial function and permeability properties in males and suggest that estrogen deficiency may represent a novel positive regulator of Bcl-2 and ANT2 proteins, two inhibitors of MPT occurrence and powerful antiapoptotic molecules.
Moro
Loredana
L
Institute of Biomembranes and Bioenergetics, National Research Council, Via Amendola 165/A, 70126 Bari, Italy. l.moro@ibbe.cnr.it
Arbini
Arnaldo A
AA
Hsieh
Jer-Tsong
JT
Ford
Jeffery
J
Simpson
Evan R
ER
Hajibeigi
Asghar
A
Oz
Orhan K
OK
D033742:Adenine Nucleotide Translocator 2 / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001141:Aromatase / Q000235:genetics*; D015153:Blotting, Western; D002308:Cardiolipins / Q000378:metabolism; D002458:Cell Fractionation; D003576:Electron Transport Complex IV / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism*; D009929:Organ Size / Q000235:genetics; D010539:Permeability / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D033742:Adenine Nucleotide Translocator 2; D002308:Cardiolipins; D033681:Mitochondrial Membrane Transport Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D004958:Estradiol; D000255:Adenosine Triphosphate; D001141:Aromatase; D003576:Electron Transport Complex IV