State-of-the-Art Paper
Mitochondria as a Therapeutic Target in Heart Failure

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Heart failure is a pressing public health problem with no curative treatment currently available. The existing therapies provide symptomatic relief, but are unable to reverse molecular changes that occur in cardiomyocytes. The mechanisms of heart failure are complex and multiple, but mitochondrial dysfunction appears to be a critical factor in the development of this disease. Thus, it is important to focus research efforts on targeting mitochondrial dysfunction in the failing heart to revive the myocardium and its contractile function. This review highlights the 3 promising areas for the development of heart failure therapies, including mitochondrial biogenesis, mitochondrial oxidative stress, and mitochondrial iron handling. Moreover, the translational potential of compounds targeting these pathways is discussed.

Key Words

cardiomyocytes
heart failure
mitochondria

Abbreviations and Acronyms

AMPK
adenosine monophosphate kinase
ATII
angiotensin receptor II
ATP
adenosine triphosphate
cGMP
cyclic guanosine monophosphate
DFP
deferiprone
eNOS
endothelial nitric oxide synthase
Fe/S
iron/sulfur
FRDA
Friedrich's ataxia
HF
heart failure
I/R
ischemia/reperfusion
MI
myocardial infarction
MnSOD
manganese superoxide dismutase
mtDNA
mitochondrial DNA
NO
nitric oxide
Nox
nicotinamide adenine dinucleotide phosphate (reduced form) oxidase
NRF
nuclear respiratory factor
PDE
phosphodiesterase
PDE5I
phosphodiesterase type 5 inhibitor
PGC1α
peroxisome proliferator–activated receptor gamma coactivator 1α
ROS
reactive oxygen species
SOD
superoxide dismutase
SS
Szeto-Schiller
Tfam
transcription factor A
TPP
triphenylphosphonium

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This work was supported, in part, by grants from the National Institutes of HealthK02 HL107448, R01 HL104181, and 1P01 HL108795 (to Dr. Ardehali). Dr. Gheorghiade is a consultant for Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd., CorThera, Cytokinetics, CytoPherx, Inc., DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Inc., Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, sanofi-aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc., and Trevena Therapeutics; and has received significant (>$10,000) support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, and Takeda Pharmaceuticals North America, Inc. Dr. Ardehali is a consultamt for Cubist Pharma, Novartis, and the Gerson Lehman Group, and is a speaker for Merck. Dr. Bayeva has reported that she has no relationships relevant to the contents of this paper to disclose.