Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress.
OBJECTIVE
We investigate the role of mitochondrial oxidative stress in mitochondrial proteome remodelling using mouse models of heart failure induced by pressure overload.


RESULTS
We demonstrate that mice overexpressing catalase targeted to mitochondria (mCAT) attenuate pressure overload-induced heart failure. An improved method of label-free unbiased analysis of the mitochondrial proteome was applied to the mouse model of heart failure induced by transverse aortic constriction (TAC). A total of 425 mitochondrial proteins were compared between wild-type and mCAT mice receiving TAC or sham surgery. The changes in the mitochondrial proteome in heart failure included decreased abundance of proteins involved in fatty acid metabolism, an increased abundance of proteins in glycolysis, apoptosis, mitochondrial unfolded protein response and proteolysis, transcription and translational control, and developmental processes as well as responses to stimuli. Overexpression of mCAT better preserved proteins involved in fatty acid metabolism and attenuated the increases in apoptotic and proteolytic enzymes. Interestingly, gene ontology analysis also showed that monosaccharide metabolic processes and protein folding/proteolysis were only overrepresented in mCAT but not in wild-type mice in response to TAC.


CONCLUSIONS
This is the first study to demonstrate that scavenging mitochondrial reactive oxygen species (ROS) by mCAT not only attenuates most of the mitochondrial proteome changes in heart failure, but also induces a subset of unique alterations. These changes represent processes that are adaptive to the increased work and metabolic requirements of pressure overload, but which are normally inhibited by overproduction of mitochondrial ROS.
Department of Pathology, University of Washington, Seattle, 98195, USA.
Dao-Fu
DF
Dai
Edward J
EJ
Hsieh
Yonggang
Y
Liu
Tony
T
Chen
Richard P
RP
Beyer
Michael T
MT
Chin
Michael J
MJ
MacCoss
Peter S
PS
Rabinovitch
D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D020543:Proteome / Q000378:metabolism
D024101:Mitochondrial Proteins; D020543:Proteome; D002374:Catalase