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Comprehensive Metabolic Profiling of Age-Related Mitochondrial Dysfunction in the High-Fat-Fed ob/ob Mouse Heart

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    Comprehensive Metabolic Profiling of Age-Related Mitochondrial Dysfunction in the High-Fat-Fed ob/ob Mouse Heart
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    † Department of Biochemistry & Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, CB2 1GA, U.K.
    ‡ MRC, Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL, U.K.
    § Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3DY, U.K.
    *E-mail: [email protected]. Tel.: +44 (0)1223 437503.
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    Journal of Proteome Research

    Cite this: J. Proteome Res. 2015, 14, 7, 2849–2862
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    https://doi.org/10.1021/acs.jproteome.5b00128
    Published May 19, 2015
    Copyright © 2015 American Chemical Society
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    Abstract

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    The ectopic deposition of fat is thought to lead to lipotoxicity and has been associated with mitochondrial dysfunction and diabetic cardiomyopathy. We have measured mitochondrial respiratory capacities in the hearts of ob/ob and wild-type mice on either a regular chow (RCD) or high-fat (HFD) diet across four age groups to investigate the impact of diet and age on mitochondrial function alongside a comprehensive strategy for metabolic profiling of the tissue. Myocardial mitochondrial dysfunction was only evident in ob/ob mice on RCD at 14 months, but it was detectable at 3 months on the HFD. Liquid chromatography–mass spectrometry (LC–MS) was used to study the profiles of acylcarnitines and the accumulation of triglycerides, but neither class of lipid was associated with mitochondrial dysfunction. However, a targeted LC–MS/MS analysis of markers of oxidative stress demonstrated increases in GSSG/GSH and 8-oxoguanine, in addition to the accumulation of diacylglycerols, which are lipid species linked to lipotoxicity. Our results demonstrate that myocardial mitochondria in ob/ob mice on RCD maintained a similar respiratory capacity to that of wild type until a late stage in aging. However, on a HFD, unlike wild-type mice, ob/ob mice failed to increase mitochondrial respiration, which may be associated with a complex I defect following increased oxidative damage.

    Copyright © 2015 American Chemical Society

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    Supporting Information

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    Figure S1: Schematic of the study design. Figure S2: Mitochondrial respiratory capacity of metabolizing fatty acids in saponin-permeabilized cardiac fibers and soleus fibers from ob/ob mice and wild-type (WT) controls on a regular chow diet. Figure S3: Summary of protein expressions of complex I, II, III, IV, and V of the electron transport chain and citrate synthase in 10 month old animals fed either regular chow diet (RCD) or high-fat diet (HFD). Table S1: The composition of total fatty acids from regular chow diet (RCD) and high-fat diet (HFD) measured by GC–MS. Table S2: Plasma insulin and glucose levels in ob/ob and wild-type mice. Table S3: Semiquantitative analysis of acyl-carnitines by LC–MS. Table S4: Biochemical names of acylcarnitines. Table S5: Genotype- and diet-induced changes of acylcarnitines profiles under different ages. Table S6: To examine lipidomic changes, LC–MS data was processed using OPLS-DA, CV-ANOVA was applied to ensure that these models were not overfitted, and the statistics for each model are displayed in this table. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jproteome.5b00128.

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    Journal of Proteome Research

    Cite this: J. Proteome Res. 2015, 14, 7, 2849–2862
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jproteome.5b00128
    Published May 19, 2015
    Copyright © 2015 American Chemical Society
    Request reuse permissions

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