Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide

Figures

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  Fig. 1. Panel A: Pathway whereby sympathetic drive mediates MITO biogenesis. Panel B: Dogs with HF had increased PNE and decreased levels of eNOS, NO, cGMP, and PGC-1α compared with NL. Treatment of HF dogs with ELAM (HF + ELAM) reversed these abnormalities. cGMP = cyclic guanosine monophosphate; du = densitometric units; ELAM = elamipretide; eNOS = endothelial nitric oxide synthase; HF = heart failure; HF-CON = dogs with HF who served as controls; HF + ELAM = dogs with HF who received treatment with ELAM; MITO = mitochondrial; NL = normal animals; NO = nitric oxide; PGC-1α = peroxisome proliferator-activated receptor gamma coactivator 1α; PNE = plasma norepinephrine

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  Fig. 2. Fusion-mediating proteins include dominant OPA-1 and Mfn2 while fission-mediating proteins include Fis-1 and Drp-1. Drp-1 = dynamin-related protein-1; Fis-1 = fission-1; Mfn2 = mitofusin-2; OPA-1 = optic atrophyy-1

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  Fig. 3. Levels of fusion-mediating proteins (i.e., OPA-1 and Mfn2) and fission-mediating proteins (i.e., Fis-1 and Drp-1) in DNR human hearts compared with human hearts with HF due to ICM and DCM. DCM = idiopathic dilated cardiomyopathy; DNR = normal donor; Drp-1 = dynamin-related protein-1; du = densitometric units; Fis-1 = fission-1; HF = heart failure; ICM = ischemic cardiomyopathy; Mfn2 = mitofusin-2; NL = normal animals; OPA-1 = optic atrophyy-1

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  Fig. 4. Levels of the regulatory protein mitofilin and the control protein GAPDH in DNR human hearts compared with human hearts with HF due to ICM and DCM (top panels) and in NL dogs, dogs with HF (HF-CON), and dogs with HF treated with ELAM (HF + ELAM; bottom panels). DCM = idiopathic dilated cardiomyopathy; DNR = normal donor; du = densitometric units; ELAM = elamipretide; GAPDH = glyceraldehyde 3-phosphate dehydrogenase; HF = heart failure; HF-CON = dogs with HF who served as controls; HF + ELAM = dogs with HF who received treatment with ELAM; ICM = ischemic cardiomyopathy; NL = normal animals

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  Fig. 5. Levels of fusion-mediating proteins (i.e., OPA-1 and Mfn2) and fission-mediating proteins (i.e., Fis-1 and Drp-1) in NL dogs, dogs with HF (HF-CON), and dogs with HF treated with ELAM (HF + ELAM). Drp-1 = dynamin-related protein-1; du = densitometric units; Fis-1 = fission-1; HF = heart failure; HF-CON = dogs with HF who served as controls; HF + ELAM = dogs with HF who received treatment with ELAM; Mfn2 = mitofusin-2; NL = normal animals; OPA-1 = optic atrophyy-1

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  Fig. 6. Levels of CL species ([18:2]2 CL), CLS-1, and the CL remodeling enzymes TAZ-1 and ALCAT-1 in NL dogs, dogs with HF (HF-CON), and dogs with HF treated with ELAM (HF + ELAM). ALCAT-1 = acyl-CoA:lysocardiolipin acyltransferase-1; CL = cardiolipin; CLS-1 = cardiolipin synthase-1; du = densitometric units; ELAM = elamipretide; HF = heart failure; HF-CON = dogs with HF who served as controls; HF + ELAM = dogs with HF who received treatment with ELAM; MITO = mitochondrial; NL = normal animals; TAZ-1 = tafazzin-1