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Review
. 2010 Feb;48(2):310-21.
doi: 10.1016/j.yjmcc.2009.09.004. Epub 2009 Sep 18.

Alterations in mitochondrial function as a harbinger of cardiomyopathy: lessons from the dystrophic heart

Yan Burelle  1 , Maya Khairallah, Alexis Ascah, Bruce G Allen, Christian F Deschepper, Basil J Petrof, Christine Des Rosiers
Affiliations
Review

Alterations in mitochondrial function as a harbinger of cardiomyopathy: lessons from the dystrophic heart

Yan Burelle et al. J Mol Cell Cardiol. 2010 Feb.

Abstract

While compelling evidence supports the central role of mitochondrial dysfunction in the pathogenesis of heart failure, there is comparatively less information available on mitochondrial alterations that occur prior to failure. Building on our recent work with the dystrophin-deficient mdx mouse heart, this review focuses on how early changes in mitochondrial functional phenotype occur prior to overt cardiomyopathy and may be a determinant for the development of adverse cardiac remodelling leading to failure. These include alterations in energy substrate utilization and signalling of cell death through increased permeability of mitochondrial membranes, which may result from abnormal calcium handling, and production of reactive oxygen species. Furthermore, we will discuss evidence supporting the notion that these alterations in the dystrophin-deficient heart may represent an early "subclinical" signature of a defective nitric oxide/cGMP signalling pathway, as well as the potential benefit of mitochondria-targeted therapies. While the mdx mouse is an animal model of Duchenne muscular dystrophy (DMD), changes in the structural integrity of dystrophin, the mutated cytoskeletal protein responsible for DMD, have also recently been implicated as a common mechanism for contractile dysfunction in heart failure. In fact, altogether our findings support a critical role for dystrophin in maintaining optimal coupling between metabolism and contraction in the heart.

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Figures

Fig. 1
Fig. 1
Mitochondrial vulnerability to permeability transition pore (PTP) opening in 12 week-old mdx mice. PTP opening was quantified in situ in isolated Langendorff perfused hearts from mdx and C57BL/10 mice using an adaptation of the mitochondrial [3H]-2-deoxyglucose (DOG) entrapment technique previously described for rat hearts [113,119]. As depicted in (A), this method relies on the fact that [3H]DOG accumulates in the cytosol of cardiomyocytes as [3H]DOG-6-phosphate (P) and does not enter mitochondria unless PTP opening occurs. Therefore, quantification of [3H]DOG-6P levels in mitochondria isolated at the end of perfusion provides a quantitative index of the number of mitochondria in which PTP opening occurred during the experiment. Specifically, hearts from control and mdx mice were initially perfused for 15 min in the nonrecirculating mode with a buffer containing 11 mM glucose, 1.5 mM lactate, 0.2 mM pyruvate, 0.8 nM insulin and 0.5 mM [3H]DOG (10 μCi/mL) to load the cardiomyocytes with this tracer. Then, following a 5-min washout of extracellular [3H]DOG, hearts were submitted to 20 min of low-flow ischemia (10% initial coronary flow) followed by 40 min reperfusion in presence of 1 μM norepinephrine. Prior to ischemia (I), mdx hearts showed no major contractile dysfunction as reflected by the rate pressure product (RPP= Left ventricular developed pressure in mm Hg×heart rate in beats per min) (C) but released greater amounts of lactate dehydrogenase (LDH; values normalized for contractile function) in the coronary effluent compared to controls (D). However, at reperfusion (R), mdx heart displayed (i) poorer functional recovery (C), (ii) enhanced LDH release (D), (iii) greater opening of the PTP (B), and (iv) greater release of cytochrome c (Cyt-c) into the cytosolic fraction (E). Data represent means±SEM, n= 10–11 per group. *p< 0.05 vs. control C57BL/10 mice.
Fig. 2
Fig. 2
Mitochondrial oxidative stress in mdx mouse hearts. (A) shows the activity of the mitochondrial oxidative stress marker, aconitase, measured in tissue homogenates prepared from either freshly isolated 12-week-old mouse hearts or perfused ex vivo in the working mode [8]. Data are expressed in percentage of values measured in control animals (C57BL/10) and represent means ± SEM, n= 6–11 per group. (B) shows the results of experiments in which changes in respiration (JO2) were recorded in response to the sequential addition of glutamate–malate (5:2.5 mM), ADP (1 mM), rotenone (1 μM), succinate (5 mM), and carbonyl cyanide m-chlorophenylhydrazone (CCCP: 0.1 μM). Data shown in (B) are expressed per mg of total protein and represent means ± SEM, n= 4–6 per group. *p< 0.05 vs. control C57BL/10 mice.
Fig. 3
Fig. 3
Simplified integrated mechanistic scheme of potential players and consequences of early mitochondrial dysfunction in the dystrophin-deficient heart. Refer to Section 6 for details. Abbreviations: nNOS, neuronal nitric oxide synthase; Ca2+, calcium; cGMP, cyclic guanosine monophosphate; PTP, permeability transition pore; CAC, citric acid cycle.
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