Modulation of mitochondrial proteome and improved mitochondrial function by biventricular pacing of dyssynchronous failing hearts.
BACKGROUND
Cardiac resynchronization therapy (CRT) improves chamber mechanoenergetics and morbidity and mortality of patients manifesting heart failure with ventricular dyssynchrony; however, little is known about the molecular changes underlying CRT benefits. We hypothesized that mitochondria may play an important role because of their involvement in energy production.


RESULTS
Mitochondria isolated from the left ventricle in a canine model of dyssynchronous or resynchronized (CRT) heart failure were analyzed by a classical, gel-based, proteomic approach. Two-dimensional gel electrophoresis revealed that 31 mitochondrial proteins where changed when controlling the false discovery rate at 30%. Key enzymes in anaplerotic pathways, such as pyruvate carboxylation and branched-chain amino acid oxidation, were increased. These concerted changes, along with others, suggested that CRT may increase the pool of Krebs cycle intermediates and fuel oxidative phosphorylation. Nearly 50% of observed changes pertained to subunits of the respiratory chain. ATP synthase-beta subunit of complex V was less degraded, and its phosphorylation modulated by CRT was associated with increased formation (2-fold, P=0.004) and specific activity (+20%, P=0.05) of the mature complex. The importance of these modifications was supported by coordinated changes in mitochondrial chaperones and proteases. CRT increased the mitochondrial respiratory control index with tightened coupling when isolated mitochondria were reexposed to substrates for both complex I (glutamate and malate) and complex II (succinate), an effect likely related to ATP synthase subunit modifications and complex quantity and activity.


CONCLUSIONS
CRT potently affects both the mitochondrial proteome and the performance associated with improved cardiac function.
Agnetti
Giulio
G
Johns Hopkins Bayview Proteomics Center, Baltimore, MD 21224, USA.
Kaludercic
Nina
N
Kane
Lesley A
LA
Elliott
Steven T
ST
Guo
Yurong
Y
Chakir
Khalid
K
Samantapudi
Daya
D
Paolocci
Nazareno
N
Tomaselli
Gordon F
GF
Kass
David A
DA
Van Eyk
Jennifer E
JE
D025181:ATP Synthetase Complexes / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002304:Cardiac Pacing, Artificial; D002952:Citric Acid Cycle; D004285:Dogs; D015180:Electrophoresis, Gel, Two-Dimensional; D006333:Heart Failure / Q000378:metabolism / Q000628:therapy*; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D020543:Proteome; D040901:Proteomics
D024101:Mitochondrial Proteins; D020543:Proteome; D025181:ATP Synthetase Complexes