Abstract
PurposeAbnormalities of MITO dynamics occur in HF and have been implicated in disease progression. This study describes the broad range abnormalities of mitochondrial (MITO) dynamics in Heart Failure with reduced ejection fraction (HF) and evaluates the effects of long-term therapy with elamipretide (ELAM), a MITO-targeting peptide, on these abnormalities.MethodsStudies were performed in left ventricular tissue from dogs and humans with HF, and were compared with tissue from healthy dogs and healthy donor human hearts. Dogs with HF were randomized to 3 months therapy with ELAM or vehicle. The following were evaluated in dog and human hearts: (1) regulators of MITO biogenesis, including endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α, a transcription factor that drives MITO biogenesis); (2) regulators of MITO fission and fusion, including fission-1, dynamin-related protein-1, mitofusion-2, dominant optic atrophy-1, and mitofilin; and (3) determinants of cardiolipin (CL) synthesis and remodeling, including CL synthase-1, tafazzin-1, and acyl-CoA:lysocardiolipin acyltransferase-1.ResultsThe study showed decreased levels of eNOS, cGMP, and PGC-1α in HF (dog and human). Increased levels of fission-associated proteins, decreased levels of fusion-associated proteins, decreased mitofilin, and abnormalities of CL synthesis and remodeling were also observed. In all instances, these maladaptations were normalized following long-term therapy with ELAM.ConclusionsCritical abnormalities of MITO dynamics occur in HF and are normalized following long-term therapy with ELAM. The findings provide support for the continued development of ELAM for the treatment of HF.
Highlights
Mitochondria (MITO) are organelles with a well-known role in cellular metabolism and energy production, but they play a critical role in cell growth and differentiation, cell signaling, and cell death or apoptosis [1, 2]
Studies of measures of MITO dynamics in tissue from explanted failed human hearts were conducted to ensure that the abnormalities seen in human tissue were consistent with those seen in dogs with experimentally induced heart failure (HF)
There was a marked degree of dysregulation with respect to proteins directly involved in the dynamics of MITO fission and fusion
Summary
Mitochondria (MITO) are organelles with a well-known role in cellular metabolism and energy production, but they play a critical role in cell growth and differentiation, cell signaling, and cell death or apoptosis [1, 2]. Once thought of as inert, mitochondria are known to be highly dynamic, constantly undergoing biogenesis, fission and fusion in response to changes in energy demands [2, 3]. The failing heart shows to dysregulation in both fission and fusion regulating proteins, and downregulation of MITO fusion proteins enhances apoptosis; a possible contributor to ongoing cardiomyocyte loss [3] and potential mediator of progressive worsening of the HF state [4, 5].
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