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MTP-131, a cardiolipin-targeting peptide, improves mitochondrial activity in the failing human heart

Session Rapid Fire 3 - Chronic heart failure management

Speaker Brian Stauffer

Congress : Heart Failure 2016

  • Topic : coronary artery disease, acute coronary syndromes, acute cardiac care
  • Sub-topic : Coronary Artery Disease (Chronic)
  • Session type : Rapid Fire Abstracts
  • FP Number : 1238

Authors : B Stauffer (Aurora,US), G Sparagna (Aurora,US), S Chau (Aurora,US), J Rodegheri-Brito (Aurora,US), A Ambardekar (Aurora,US), A Korst (Aurora,US), S Miyamoto (Aurora,US), C Sucharov (Aurora,US), K Chatfield (Aurora,US)


B Stauffer1 , G Sparagna1 , S Chau1 , J Rodegheri-Brito1 , A Ambardekar1 , A Korst1 , S Miyamoto2 , C Sucharov1 , K Chatfield2 , 1University of Colorado, Medicine/Cardiology - Aurora - United States of America , 2University of Colorado, Pediatrics/Cardiology - Aurora - United States of America ,

European Journal of Heart Failure Abstracts Supplement ( 2016 ) 18 ( Supplement 1 ), 289

Background: Mitochondrial dysfunction contributes to myocellular abnormalities in the failing human heart. We have previously shown significant abnormalities in cardiolipin content and electron transport chain complexes in failing human heart. MTP-131 (elamipretide) is a mitochondria-targeting peptide currently being investigated in several Phase 2 clinical trials for heart failure. In animal models of heart disease, MTP-131 improved cardiac and mitochondrial function through a mechanism involving stabilization of cardiolipin-dependent respiration. Purpose: To determine whether MTP-131 treatment of the human failing heart improves mitochondrial function, assessed at different sites along the respiratory chain. Methods: Ventricular tissue was rapidly harvested at the time of cardiac transplantation for end-stage heart failure secondary to idiopathic dilated cardiomyopathy (F), or from age-matched donor hearts (NF) not implanted for technical reasons. Tissue was either immediately used for respirometry or rapidly frozen at -80C. In fresh tissue, mitochondrial Complex I- and II-dependent respiration was determined using high-resolution respirometry. Total Complex IV activity was determined using spectrophotometric assays. From frozen samples, Complex IV in-gel activity assays were performed in Blue Native (BN)-PAGE to determine activity attributed to within the supercomplex (SCIV) or from uncomplexed, free Complex IV (FCIV). Results: State 3 respiration (in pmol/(s*mg)) was lower in F than NF when mitochondria were respiring via Complex I- or II-dependent substrates (glutamate/malate: 40 ± 11 vs 75 ± 6; succinate: 64 ± 16 vs 108 ± 11). MTP-131 treatment improved state 3 respiration in F mitochondria at both complexes I and II (glutamate/malate: 74 ± 6; succinate: 125 ± 13), but did not alter respiration in NF mitochondria under any substrate conditions. In BN-PAGE studies, SCIV activity was 30% lower (P < 0.05) in F compared to NF-samples, but unchanged in the FCIV fraction. MTP-131 treatment increased SCIV activity (P < 0.05) but did not change FCIV activity, suggesting that MTP-131-mediated improvements in respiration occur in mitochondrial supercomplexes. MTP-131 treatment of freshly-isolated F mitochondria increased Complex IV activity by 50% (P < 0.01). Conclusion: MTP-131 treatment improves mitochondrial function at the level of the individual complex, supercomplex and intact mitochondria in the failing human heart. These findings suggest that stabilizing cardiolipin-dependent respiratory complexes represents a novel treatment for improving mitochondrial function in heart failure.

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