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Mechanisms of reduced mitochondrial Ca2+ accumulation in failing hamster heart

  • Cardiovascular System
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Abstract

Mitochondrial Ca2+ plays important roles in the regulation of energy metabolism and cellular Ca2+ homeostasis. In this study, we characterized mitochondrial Ca2+ accumulation in Syrian hamster hearts with hereditary cardiomyopathy (strain BIO 14.6). Exposure of isolated mitochondria from 70 nM to 30 μM Ca2+ ([Ca2+]o) caused a concentration-dependent increase in intramitochondrial Ca2+ concentrations ([Ca2+]m). The [Ca2+]m was significantly lower in cardiomyopathic (CMP) hamsters than in healthy hamsters when [Ca2+]o was higher than 1 μM and a decrease of about 52% was detected at [Ca2+]o of 30 μM (916 ± 67 nM vs 1,932 ± 132 nM in control). A possible mechanism responsible for the decreased mitochondrial Ca2+ uptake in CMP hamsters is the depolarization of mitochondrial membrane potential (Δψ m). Using a tetraphenylphosphonium (TPP+) electrode, the measured Δψ m in failing heart mitochondria was −136 ± 1.5 mV compared with −159 ± 1.3 mV in controls. Analyses of mitochondrial respiratory chain demonstrated a significant impairment of complex I and complex IV activities in failing heart mitochondria. In summary, a less negative Δψ m resulting from defects in the respiratory chain may lead to attenuated mitochondrial Ca2+ accumulation, which in turn may contribute to the depressed energy production and myocardial contractility in this model of heart failure. In addition to other known impairments of ion transport in sarcoplasmic reticulum and plasma membrane, results from this paper on mitochondrial dysfunctions expand our understanding of the molecular mechanisms leading to heart failure.

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Acknowledgements

This work was supported by NIH grants HL-33333 and American Heart Association/New York State Affiliate Grant-in-aid 0050839T. We thank everyone in Dr. Sheu’s laboratory and Dr. Paul Brookes and Dr.Robert Dirksen for helpful discussion on the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Box 711, Rochester, NY, 14642, USA

    Lin Lin, Virendra K. Sharma & Shey-Shing Sheu

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  1. Lin Lin
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  2. Virendra K. Sharma
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  3. Shey-Shing Sheu
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Correspondence to Shey-Shing Sheu.

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Lin, L., Sharma, V.K. & Sheu, SS. Mechanisms of reduced mitochondrial Ca2+ accumulation in failing hamster heart. Pflugers Arch - Eur J Physiol 454, 395–402 (2007). https://doi.org/10.1007/s00424-007-0257-8

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  • DOI: https://doi.org/10.1007/s00424-007-0257-8

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