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Chicco 2016c Abstract MitoFit Science Camp 2016 - Revision history
2024-03-28T13:06:37Z
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https://wiki.oroboros.at/index.php?title=Chicco_2016c_Abstract_MitoFit_Science_Camp_2016&diff=144433&oldid=prev
Beno Marija at 13:34, 20 October 2017
2017-10-20T13:34:07Z
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<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>== Abstract continued ==</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>== Abstract continued ==</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>Taken together, our studies suggest a contributory role of CoA deficiency in Taz-deficient cardiac mitochondrial dysfunction, with potential implications for future study and treatment of BTHS. More broadly, these results highlight the value of comprehensive mitochondrial respirometry and enzyme analysis as means of defining sites of OXPHOS impairment in mitochondrial pathologies as established by Hoppel [2], and the importance of considering the metabolic pathways of respiratory substrates upstream of their associated sites of entry to electron transfer <del style="font-weight: bold; text-decoration: none;">system</del>. In particular, comparison of OXPHOS rates obtained with glutamate versus pyruvate, which are often used interchangeably as CI substrates, might reveal important insights relevant to the mechanisms of mitochondrial adaptation in health and disease. </div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>Taken together, our studies suggest a contributory role of CoA deficiency in Taz-deficient cardiac mitochondrial dysfunction, with potential implications for future study and treatment of BTHS. More broadly, these results highlight the value of comprehensive mitochondrial respirometry and enzyme analysis as means of defining sites of OXPHOS impairment in mitochondrial pathologies as established by Hoppel [2], and the importance of considering the metabolic pathways of respiratory substrates upstream of their associated sites of entry to electron transfer<ins style="font-weight: bold; text-decoration: none;">-pathway</ins>. In particular, comparison of OXPHOS rates obtained with glutamate versus pyruvate, which are often used interchangeably as CI substrates, might reveal important insights relevant to the mechanisms of mitochondrial adaptation in health and disease. </div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>== References ==</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>== References ==</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>#Raja V, Greenberg ML (2014) The functions of cardiolipin in cellular metabolism-potential modifiers of the Barth syndrome phenotype. Chem Phys Lipids 179:49.</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>#Raja V, Greenberg ML (2014) The functions of cardiolipin in cellular metabolism-potential modifiers of the Barth syndrome phenotype. Chem Phys Lipids 179:49.</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>#Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria--case studies. Mitochondrion 4:377.</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>#Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria--case studies. Mitochondrion 4:377.</div></td></tr>
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Beno Marija
https://wiki.oroboros.at/index.php?title=Chicco_2016c_Abstract_MitoFit_Science_Camp_2016&diff=123305&oldid=prev
Beno Marija at 13:59, 7 November 2016
2016-11-07T13:59:39Z
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Beno Marija
https://wiki.oroboros.at/index.php?title=Chicco_2016c_Abstract_MitoFit_Science_Camp_2016&diff=115071&oldid=prev
Kandolf Georg at 07:09, 1 July 2016
2016-07-01T07:09:56Z
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Kandolf Georg
https://wiki.oroboros.at/index.php?title=Chicco_2016c_Abstract_MitoFit_Science_Camp_2016&diff=114831&oldid=prev
Gnaiger Erich at 11:09, 28 June 2016
2016-06-28T11:09:29Z
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<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|title=Investigating the mechanism of cardiac mitochondrial respiratory impairment in Barth Syndrome.</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|title=Investigating the mechanism of cardiac mitochondrial respiratory impairment in Barth Syndrome.</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|info=[[File:ChiccoA.jpg|150px|right|Adam Chicco]]</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|info=[[File:ChiccoA.jpg|150px|right|Adam Chicco]]</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|authors=Chicco <del style="font-weight: bold; text-decoration: none;">Adam J</del>, Le CH, Benage LG, Prenni JE, Heuberger AL</div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|authors=Chicco <ins style="font-weight: bold; text-decoration: none;">AJ</ins>, Le CH, Benage LG, Prenni JE, Heuberger AL</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|year=2016</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|year=2016</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|event=MitoFit Science Camp 2016 Kuehtai AT</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|event=MitoFit Science Camp 2016 Kuehtai AT</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|abstract=Barth Syndrome (3-methylglutaconic aciduria type II; BTHS) is a childhood onset cardioskeletal myopathy that results from mutations in the tafazzin gene encoding a phospholipid transacylase responsible for remodeling cardiolipin in the inner mitochondrial membrane. Cardiolipin is known to be required for optimal function and assembly of respiratory supercomplexes in the inner membrane, but precisely how loss of tafazzin function impairs mitochondrial respiratory function leading to BTHS is unclear. We utilized high resolution respirometry (HHR) with a variety of substrate combinations to investigate the sites of cardiac mitochondrial dysfunction in the tafazzin shRNA (Taz) mouse model of BTHS, which exhibits ~90% tafazzin deficiency and cardiolipin abnormalities characteristic of BTHS in humans. </div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|abstract=Barth Syndrome (3-methylglutaconic aciduria type II; BTHS) is a childhood onset cardioskeletal myopathy that results from mutations in the tafazzin gene encoding a phospholipid transacylase responsible for remodeling cardiolipin in the inner mitochondrial membrane. Cardiolipin is known to be required for optimal function and assembly of respiratory supercomplexes in the inner membrane, but precisely how loss of tafazzin function impairs mitochondrial respiratory function leading to BTHS is unclear. We utilized high<ins style="font-weight: bold; text-decoration: none;">-</ins>resolution respirometry (HHR) with a variety of substrate combinations to investigate the sites of cardiac mitochondrial dysfunction in the tafazzin shRNA (Taz) mouse model of BTHS, which exhibits ~90% tafazzin deficiency and cardiolipin abnormalities characteristic of BTHS in humans. </div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>Initial HRR studies revealed 50% lower rates of Complex I (CI)-linked OXPHOS respiration in Taz mitochondria compared to wild-type (WT) controls using pyruvate <del style="font-weight: bold; text-decoration: none;">+ </del>malate as substrates, while succinate (CII)-supported OXPHOS and maximal enzymatic capacities of complexes I, II-IV and IV were only suppressed by 12-20%. Surprisingly, CI-linked OXPHOS supported by glutamate <del style="font-weight: bold; text-decoration: none;">+ </del>malate was 50% higher in Taz, approximating rates of maximal pyruvate-supported OXPHOS in WT, arguing against CI as a primary site of OXPHOS limitation in Taz. To investigate fatty acid-supported OXPHOS, <del style="font-weight: bold; text-decoration: none;"> </del>long- (16:0; palmitate) and medium-chain (8:0; octanoate) fatty acids were supplied bound to carnitine (CPT1-independent) or CoA (CPT1-dependent) to address effects on mitochondrial fatty acid transport, activation and acyl-CoA dehydrogenase isozyme-specific function [1]. </div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>Initial HRR studies revealed 50% lower rates of Complex I (CI)-linked OXPHOS respiration in Taz mitochondria compared to wild-type (WT) controls using pyruvate <ins style="font-weight: bold; text-decoration: none;">& </ins>malate as substrates, while succinate (CII)-supported OXPHOS and maximal enzymatic capacities of complexes I, II-IV and IV were only suppressed by 12-20%. Surprisingly, CI-linked OXPHOS supported by glutamate <ins style="font-weight: bold; text-decoration: none;">& </ins>malate was 50% higher in Taz, approximating rates of maximal pyruvate-supported OXPHOS in WT, arguing against CI as a primary site of OXPHOS limitation in Taz. To investigate fatty acid-supported OXPHOS, long- (16:0; palmitate) and medium-chain (8:0; octanoate) fatty acids were supplied bound to carnitine (CPT1-independent) or CoA (CPT1-dependent) to address effects on mitochondrial fatty acid transport, activation and acyl-CoA dehydrogenase isozyme-specific function [1]. </div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>Results demonstrated significant impairment of respiration supported by both medium and long-chain acyl-carnitines in Taz compared to WT mitochondria, which was blunted when palmitoyl-CoA <del style="font-weight: bold; text-decoration: none;">+ </del>carnitine were used as substrates. Interestingly, metabolomic analysis of cardiac tissues revealed an 41% decrease in pantothenic acid that corresponded to a similar loss of mitochondrial CoA content in Taz compared to WT hearts. To test the hypothesis that CoA deficiency limits pyruvate and fatty acid oxidation in Taz, mitochondria were pre-incubated with 100 μM CoA to restore levels prior to repeating HRR experiments with pyruvate or palmitoylcarnitine (<del style="font-weight: bold; text-decoration: none;">+ </del>malate). This increased CoA content in both Taz and WT mitochondria and partially rescued OXPHOS supported by substrates to near WT levels, despite having no significant effect on OXPHOS rates with either substrate in WT.</div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>Results demonstrated significant impairment of respiration supported by both medium and long-chain acyl-carnitines in Taz compared to WT mitochondria, which was blunted when palmitoyl-CoA <ins style="font-weight: bold; text-decoration: none;">& </ins>carnitine were used as substrates. Interestingly, metabolomic analysis of cardiac tissues revealed an 41% decrease in pantothenic acid that corresponded to a similar loss of mitochondrial CoA content in Taz compared to WT hearts. To test the hypothesis that CoA deficiency limits pyruvate and fatty acid oxidation in Taz, mitochondria were pre-incubated with 100 μM CoA to restore levels prior to repeating HRR experiments with pyruvate or palmitoylcarnitine (<ins style="font-weight: bold; text-decoration: none;">& </ins>malate). This increased CoA content in both Taz and WT mitochondria and partially rescued OXPHOS supported by substrates to near WT levels, despite having no significant effect on OXPHOS rates with either substrate in WT.</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|mipnetlab=US CO Fort Collins Chicco AJ</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|mipnetlab=US CO Fort Collins Chicco AJ</div></td></tr>
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</table>
Gnaiger Erich
https://wiki.oroboros.at/index.php?title=Chicco_2016c_Abstract_MitoFit_Science_Camp_2016&diff=113018&oldid=prev
Kandolf Georg at 09:29, 7 June 2016
2016-06-07T09:29:08Z
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<td colspan="2" style="background-color: #fff; color: #202122; text-align: center;">← Older revision</td>
<td colspan="2" style="background-color: #fff; color: #202122; text-align: center;">Revision as of 09:29, 7 June 2016</td>
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<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>{{Abstract</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>{{Abstract</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|title=Investigating the mechanism of cardiac mitochondrial respiratory impairment in Barth Syndrome</div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|title=Investigating the mechanism of cardiac mitochondrial respiratory impairment in Barth Syndrome<ins style="font-weight: bold; text-decoration: none;">.</ins></div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|info=[[File:ChiccoA.jpg|150px|right|Adam Chicco]]</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|info=[[File:ChiccoA.jpg|150px|right|Adam Chicco]]</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|authors=Chicco Adam J, Le CH, Benage LG, Prenni JE, Heuberger AL</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|authors=Chicco Adam J, Le CH, Benage LG, Prenni JE, Heuberger AL</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|year=2016</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|year=2016</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|event=MitoFit Science Camp 2016 Kuehtai AT</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|event=MitoFit Science Camp 2016 Kuehtai AT</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|abstract=Barth Syndrome (3-methylglutaconic aciduria type II; BTHS) is a childhood onset cardioskeletal myopathy that results from mutations in the tafazzin gene encoding a phospholipid transacylase responsible for remodeling cardiolipin in the inner mitochondrial membrane. Cardiolipin is known to be required for optimal function and assembly of respiratory supercomplexes in the inner membrane, but precisely how loss of tafazzin function impairs mitochondrial respiratory function leading to BTHS is unclear. <del style="font-weight: bold; text-decoration: none;"> </del>We utilized high resolution respirometry (HHR) with a variety of substrate combinations to investigate the sites of cardiac mitochondrial dysfunction in the tafazzin shRNA (Taz) mouse model of BTHS, which exhibits ~90% tafazzin deficiency and cardiolipin abnormalities characteristic of BTHS in humans. </div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|abstract=Barth Syndrome (3-methylglutaconic aciduria type II; BTHS) is a childhood onset cardioskeletal myopathy that results from mutations in the tafazzin gene encoding a phospholipid transacylase responsible for remodeling cardiolipin in the inner mitochondrial membrane. Cardiolipin is known to be required for optimal function and assembly of respiratory supercomplexes in the inner membrane, but precisely how loss of tafazzin function impairs mitochondrial respiratory function leading to BTHS is unclear. We utilized high resolution respirometry (HHR) with a variety of substrate combinations to investigate the sites of cardiac mitochondrial dysfunction in the tafazzin shRNA (Taz) mouse model of BTHS, which exhibits ~90% tafazzin deficiency and cardiolipin abnormalities characteristic of BTHS in humans. </div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>Initial HRR studies revealed 50% lower rates of Complex I (CI)-linked OXPHOS respiration in Taz mitochondria compared to wild-type (WT) controls using pyruvate + malate as substrates, while succinate (CII)-supported OXPHOS and maximal enzymatic capacities of complexes I, II-IV and IV were only suppressed by 12-20%. Surprisingly, CI-linked OXPHOS supported by glutamate + malate was 50% higher in Taz, approximating rates of maximal pyruvate-supported OXPHOS in WT, arguing against CI as a primary site of OXPHOS limitation in Taz. To investigate fatty acid-supported OXPHOS, long- (16:0; palmitate) and medium-chain (8:0; octanoate) fatty acids were supplied bound to carnitine (CPT1-independent) or CoA (CPT1-dependent) to address effects on mitochondrial fatty acid transport, activation and acyl-CoA dehydrogenase isozyme-specific function [1]. <del style="font-weight: bold; text-decoration: none;"> Results demonstrated significant impairment of respiration supported by both medium and long-chain acyl-carnitines in Taz compared to WT mitochondria, which was blunted when palmitoyl-CoA + carnitine were used as substrates. Interestingly, metabolomic analysis of cardiac tissues revealed and 41% decrease in pantothenic acid that corresponded to a similar loss of mitochondrial CoA content in Taz compared to WT hearts. To test the hypothesis that CoA deficiency limits pyruvate and fatty acid oxidation in Taz, mitochondria were pre-incubated with 100 μM CoA to restore levels prior to repeating HRR experiments with pyruvate or palmitoylcarnitine (+ malate). This increased CoA content in both Taz and WT mitochondria and partially rescued OXPHOS supported by substrates to near WT levels, despite having no significant effect on OXPHOS rates with either substrate in WT. </del></div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>Initial HRR studies revealed 50% lower rates of Complex I (CI)-linked OXPHOS respiration in Taz mitochondria compared to wild-type (WT) controls using pyruvate + malate as substrates, while succinate (CII)-supported OXPHOS and maximal enzymatic capacities of complexes I, II-IV and IV were only suppressed by 12-20%. Surprisingly, CI-linked OXPHOS supported by glutamate + malate was 50% higher in Taz, approximating rates of maximal pyruvate-supported OXPHOS in WT, arguing against CI as a primary site of OXPHOS limitation in Taz. To investigate fatty acid-supported OXPHOS, long- (16:0; palmitate) and medium-chain (8:0; octanoate) fatty acids were supplied bound to carnitine (CPT1-independent) or CoA (CPT1-dependent) to address effects on mitochondrial fatty acid transport, activation and acyl-CoA dehydrogenase isozyme-specific function [1]. </div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td></tr>
<tr><td colspan="2"></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">Results demonstrated significant impairment of respiration supported by both medium and long-chain acyl-carnitines in Taz compared to WT mitochondria, which was blunted when palmitoyl-CoA + carnitine were used as substrates. Interestingly, metabolomic analysis of cardiac tissues revealed an 41% decrease in pantothenic acid that corresponded to a similar loss of mitochondrial CoA content in Taz compared to WT hearts. To test the hypothesis that CoA deficiency limits pyruvate and fatty acid oxidation in Taz, mitochondria were pre-incubated with 100 μM CoA to restore levels prior to repeating HRR experiments with pyruvate or palmitoylcarnitine (+ malate). This increased CoA content in both Taz and WT mitochondria and partially rescued OXPHOS supported by substrates to near WT levels, despite having no significant effect on OXPHOS rates with either substrate in WT.</ins></div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|mipnetlab=US CO Fort Collins Chicco AJ</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|mipnetlab=US CO Fort Collins Chicco AJ</div></td></tr>
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<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>{{Labeling</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>{{Labeling</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|area=Respiration</div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|area=Respiration<ins style="font-weight: bold; text-decoration: none;">, mt-Medicine</ins></div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|organism=Mouse</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|organism=Mouse</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|tissues=Heart<del style="font-weight: bold; text-decoration: none;">, Skeletal muscle</del></div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|tissues=Heart</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|<del style="font-weight: bold; text-decoration: none;">preparations</del>=<del style="font-weight: bold; text-decoration: none;">Permeabilized tissue, Homogenate, Isolated mitochondria</del></div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|<ins style="font-weight: bold; text-decoration: none;">diseases</ins>=<ins style="font-weight: bold; text-decoration: none;">Myopathy</ins></div></td></tr>
<tr><td colspan="2"></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">|topics=Substrate</ins></div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|couplingstates=OXPHOS</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>|couplingstates=OXPHOS</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|substratestates=CI<del style="font-weight: bold; text-decoration: none;">&II</del></div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|substratestates=CI<ins style="font-weight: bold; text-decoration: none;">, CII, FAO, CIV, Other combinations</ins></div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|instruments=Oxygraph-2k<del style="font-weight: bold; text-decoration: none;">, O2k-Fluorometer</del></div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|instruments=Oxygraph-2k</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|additional=MitoFit Science Camp 2016<del style="font-weight: bold; text-decoration: none;">, Amplex Red</del></div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|additional=MitoFit Science Camp 2016</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>}}</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>}}</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>== Affiliations ==</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>== Affiliations ==</div></td></tr>
<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l25">Line 25:</td>
<td colspan="2" class="diff-lineno">Line 27:</td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>== Abstract continued ==</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>== Abstract continued ==</div></td></tr>
<tr><td class="diff-marker" data-marker="−"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>Taken together, our studies suggest a contributory role of CoA deficiency in Taz-deficient cardiac mitochondrial dysfunction, with potential implications for future study and treatment of BTHS. <del style="font-weight: bold; text-decoration: none;"> </del>More broadly, these results highlight the value of comprehensive mitochondrial respirometry and enzyme analysis as means of defining sites of OXPHOS impairment in mitochondrial pathologies as established by Hoppel [2], and the importance of considering the metabolic pathways of respiratory substrates upstream of their associated <del style="font-weight: bold; text-decoration: none;"> </del>sites of entry to electron transfer system. In particular, comparison of OXPHOS rates obtained with glutamate versus pyruvate, which are often used interchangeably as CI substrates, might reveal important insights relevant to the mechanisms of mitochondrial adaptation in health and disease. </div></td><td class="diff-marker" data-marker="+"></td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>Taken together, our studies suggest a contributory role of CoA deficiency in Taz-deficient cardiac mitochondrial dysfunction, with potential implications for future study and treatment of BTHS. More broadly, these results highlight the value of comprehensive mitochondrial respirometry and enzyme analysis as means of defining sites of OXPHOS impairment in mitochondrial pathologies as established by Hoppel [2], and the importance of considering the metabolic pathways of respiratory substrates upstream of their associated sites of entry to electron transfer system. In particular, comparison of OXPHOS rates obtained with glutamate versus pyruvate, which are often used interchangeably as CI substrates, might reveal important insights relevant to the mechanisms of mitochondrial adaptation in health and disease. </div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><br/></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>== References ==</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>== References ==</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>#Raja V, Greenberg ML (2014) The functions of cardiolipin in cellular metabolism-potential modifiers of the Barth syndrome phenotype. Chem Phys Lipids 179:49.</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>#Raja V, Greenberg ML (2014) The functions of cardiolipin in cellular metabolism-potential modifiers of the Barth syndrome phenotype. Chem Phys Lipids 179:49.</div></td></tr>
<tr><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>#Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria--case studies. Mitochondrion 4:377.</div></td><td class="diff-marker"></td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>#Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria--case studies. Mitochondrion 4:377.</div></td></tr>
</table>
Kandolf Georg
https://wiki.oroboros.at/index.php?title=Chicco_2016c_Abstract_MitoFit_Science_Camp_2016&diff=113017&oldid=prev
Kandolf Georg: Created page with "{{Abstract |title=Investigating the mechanism of cardiac mitochondrial respiratory impairment in Barth Syndrome |info=Adam Chicco |authors=Chicco..."
2016-06-07T09:21:14Z
<p>Created page with "{{Abstract |title=Investigating the mechanism of cardiac mitochondrial respiratory impairment in Barth Syndrome |info=<a href="/index.php/File:ChiccoA.jpg" title="File:ChiccoA.jpg">150px|right|Adam Chicco</a> |authors=Chicco..."</p>
<p><b>New page</b></p><div>{{Abstract<br />
|title=Investigating the mechanism of cardiac mitochondrial respiratory impairment in Barth Syndrome<br />
|info=[[File:ChiccoA.jpg|150px|right|Adam Chicco]]<br />
|authors=Chicco Adam J, Le CH, Benage LG, Prenni JE, Heuberger AL<br />
|year=2016<br />
|event=MitoFit Science Camp 2016 Kuehtai AT<br />
|abstract=Barth Syndrome (3-methylglutaconic aciduria type II; BTHS) is a childhood onset cardioskeletal myopathy that results from mutations in the tafazzin gene encoding a phospholipid transacylase responsible for remodeling cardiolipin in the inner mitochondrial membrane. Cardiolipin is known to be required for optimal function and assembly of respiratory supercomplexes in the inner membrane, but precisely how loss of tafazzin function impairs mitochondrial respiratory function leading to BTHS is unclear. We utilized high resolution respirometry (HHR) with a variety of substrate combinations to investigate the sites of cardiac mitochondrial dysfunction in the tafazzin shRNA (Taz) mouse model of BTHS, which exhibits ~90% tafazzin deficiency and cardiolipin abnormalities characteristic of BTHS in humans. <br />
<br />
Initial HRR studies revealed 50% lower rates of Complex I (CI)-linked OXPHOS respiration in Taz mitochondria compared to wild-type (WT) controls using pyruvate + malate as substrates, while succinate (CII)-supported OXPHOS and maximal enzymatic capacities of complexes I, II-IV and IV were only suppressed by 12-20%. Surprisingly, CI-linked OXPHOS supported by glutamate + malate was 50% higher in Taz, approximating rates of maximal pyruvate-supported OXPHOS in WT, arguing against CI as a primary site of OXPHOS limitation in Taz. To investigate fatty acid-supported OXPHOS, long- (16:0; palmitate) and medium-chain (8:0; octanoate) fatty acids were supplied bound to carnitine (CPT1-independent) or CoA (CPT1-dependent) to address effects on mitochondrial fatty acid transport, activation and acyl-CoA dehydrogenase isozyme-specific function [1]. Results demonstrated significant impairment of respiration supported by both medium and long-chain acyl-carnitines in Taz compared to WT mitochondria, which was blunted when palmitoyl-CoA + carnitine were used as substrates. Interestingly, metabolomic analysis of cardiac tissues revealed and 41% decrease in pantothenic acid that corresponded to a similar loss of mitochondrial CoA content in Taz compared to WT hearts. To test the hypothesis that CoA deficiency limits pyruvate and fatty acid oxidation in Taz, mitochondria were pre-incubated with 100 μM CoA to restore levels prior to repeating HRR experiments with pyruvate or palmitoylcarnitine (+ malate). This increased CoA content in both Taz and WT mitochondria and partially rescued OXPHOS supported by substrates to near WT levels, despite having no significant effect on OXPHOS rates with either substrate in WT. <br />
<br />
|mipnetlab=US CO Fort Collins Chicco AJ<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|organism=Mouse<br />
|tissues=Heart, Skeletal muscle<br />
|preparations=Permeabilized tissue, Homogenate, Isolated mitochondria<br />
|couplingstates=OXPHOS<br />
|substratestates=CI&II<br />
|instruments=Oxygraph-2k, O2k-Fluorometer<br />
|additional=MitoFit Science Camp 2016, Amplex Red<br />
}}<br />
== Affiliations ==<br />
1-Depts. Biomedical Sci, 2-Cell Mol Biol, 3-Biochem Mol Biol, Colorado State Univ, Fort Collins, USA, CO. - Adam.Chicco@colostate.edu<br />
<br />
== Abstract continued ==<br />
Taken together, our studies suggest a contributory role of CoA deficiency in Taz-deficient cardiac mitochondrial dysfunction, with potential implications for future study and treatment of BTHS. More broadly, these results highlight the value of comprehensive mitochondrial respirometry and enzyme analysis as means of defining sites of OXPHOS impairment in mitochondrial pathologies as established by Hoppel [2], and the importance of considering the metabolic pathways of respiratory substrates upstream of their associated sites of entry to electron transfer system. In particular, comparison of OXPHOS rates obtained with glutamate versus pyruvate, which are often used interchangeably as CI substrates, might reveal important insights relevant to the mechanisms of mitochondrial adaptation in health and disease. <br />
<br />
== References ==<br />
#Raja V, Greenberg ML (2014) The functions of cardiolipin in cellular metabolism-potential modifiers of the Barth syndrome phenotype. Chem Phys Lipids 179:49.<br />
#Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria--case studies. Mitochondrion 4:377.</div>
Kandolf Georg