26-A-10540-ACC Distinct Differences among Mitochondrial Subpopulations of the Failing Heart in Their Efficiency to Generate Atp

Document Type

Conference Proceeding

Publication Date

4-7-2026

Publication Title

J Am Coll Cardiol

Abstract

Background: Mitochondria (MITO) are dysfunctional in heart failure (HF) and exhibit a range of abnormalities including impaired electron transport chain activity, increased production of damaging reactive oxygen species, and altered MITO dynamics (fission/fusion) and structure. These abnormalities can disrupt the heart's energy supply and contribute to HF progression. Cardiomyocytes possess two distinct MITO subpopulations namely, subsarcolemmal MITO (SSM) and interfibrillar MITO (IFM). Nearly 80% of ATP generated by IFM is used toward contraction and relaxation of cardiac muscle, while ATP generated by SSM is used primarily for other essential cellular processes with negligible contribution to contraction and relaxation. Hypothesis: We tested the hypothesis that pathological stresses of HF are associated with differential MITO efficiencies to generate ATP by MITO subpopulation. Methods: MITO were isolated from ∼2 g of fresh LV myocardium of 7 normal dogs (NL) and 7 dogs with chronic HF produced by intracoronary microembolizations. Following separation of SSM with differential centrifugation of the homogenate, the remaining pellet was treated with trypsin to dissociate IFM. Oxygen consumption rates (OCR) were measured in both SSM and IFM using a Seahorse Biosciences high-resolution respirometry. MITO efficiency was measured as the ratio of STATE-III/STATE-IV respiration (coupling efficiency or oxidative phosphorylation efficiency), a measure of the proportion of oxygen consumption used to produce ATP versus the amount of oxygen consumed that is not converted into energy. Results Coupling efficiency was not different in SSM of HF compared to NL dogs (3.50 ± 0.24 vs 3.96 ± 1.28; p<0.05). However, in IFM the coupling efficiency in HF dogs was nearly half that of NL dogs (5.74 ± 1.14 vs. 9.78 ± 2.18, p<0.05). Conclusion: MITO coupling efficiency is significantly reduced in IFM of HF dogs whereas SSM coupling efficiency is unchanged compared to NL dogs. These data indicate that in HF, IFM are particularly less effective at producing ATP relative to the oxygen they consume. This deficiency can adversely impact myocardial contraction and relaxation and contribute to HF disease progression.

Volume

87

Issue

13

First Page

A518

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