Differential remodelling of mitochondrial subpopulations and mitochondrial dysfunction are a feature of early stage diabetes
Abstract Mitochondrial dysfunction is a feature of type I and type II diabetes, but there is a lack of consistency between reports and links to disease development. We aimed to investigate if mitochondrial structure–function remodelling occurs in the early stages of diabetes by employing a mouse mod...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-04929-1 |
| _version_ | 1798016364048285696 |
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| author | Bodour S. Rajab Sarah Kassab Connor D. Stonall Hussam Daghistani Stephen Gibbons Mamas Mamas David Smith Aleksandr Mironov Zainab AlBalawi Yin Hua Zhang Florence Baudoin Min Zi Sukhpal Prehar Elizabeth J. Cartwright Ashraf Kitmitto |
| author_facet | Bodour S. Rajab Sarah Kassab Connor D. Stonall Hussam Daghistani Stephen Gibbons Mamas Mamas David Smith Aleksandr Mironov Zainab AlBalawi Yin Hua Zhang Florence Baudoin Min Zi Sukhpal Prehar Elizabeth J. Cartwright Ashraf Kitmitto |
| author_sort | Bodour S. Rajab |
| collection | DOAJ |
| description | Abstract Mitochondrial dysfunction is a feature of type I and type II diabetes, but there is a lack of consistency between reports and links to disease development. We aimed to investigate if mitochondrial structure–function remodelling occurs in the early stages of diabetes by employing a mouse model (GENA348) of Maturity Onset Diabetes in the Young, exhibiting hyperglycemia, but not hyperinsulinemia, with mild left ventricular dysfunction. Employing 3-D electron microscopy (SBF-SEM) we determined that compared to wild-type, WT, the GENA348 subsarcolemma mitochondria (SSM) are ~ 2-fold larger, consistent with up-regulation of fusion proteins Mfn1, Mfn2 and Opa1. Further, in comparison, GENA348 mitochondria are more irregular in shape, have more tubular projections with SSM projections being longer and wider. Mitochondrial density is also increased in the GENA348 myocardium consistent with up-regulation of PGC1-α and stalled mitophagy (down-regulation of PINK1, Parkin and Miro1). GENA348 mitochondria have more irregular cristae arrangements but cristae dimensions and density are similar to WT. GENA348 Complex activity (I, II, IV, V) activity is decreased but the OCR is increased, potentially linked to a shift towards fatty acid oxidation due to impaired glycolysis. These novel data reveal that dysregulated mitochondrial morphology, dynamics and function develop in the early stages of diabetes. |
| first_indexed | 2024-04-11T15:48:25Z |
| format | Article |
| id | doaj.art-bde8520cc3e14e259933a31d61e012ec |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T15:48:25Z |
| publishDate | 2022-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-bde8520cc3e14e259933a31d61e012ec2022-12-22T04:15:27ZengNature PortfolioScientific Reports2045-23222022-01-0112111710.1038/s41598-022-04929-1Differential remodelling of mitochondrial subpopulations and mitochondrial dysfunction are a feature of early stage diabetesBodour S. Rajab0Sarah Kassab1Connor D. Stonall2Hussam Daghistani3Stephen Gibbons4Mamas Mamas5David Smith6Aleksandr Mironov7Zainab AlBalawi8Yin Hua Zhang9Florence Baudoin10Min Zi11Sukhpal Prehar12Elizabeth J. Cartwright13Ashraf Kitmitto14Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreEM Core Facility (RRID: SCR_021147), Faculty of Biology, Medicine and Health, The University of ManchesterEM Core Facility (RRID: SCR_021147), Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreAbstract Mitochondrial dysfunction is a feature of type I and type II diabetes, but there is a lack of consistency between reports and links to disease development. We aimed to investigate if mitochondrial structure–function remodelling occurs in the early stages of diabetes by employing a mouse model (GENA348) of Maturity Onset Diabetes in the Young, exhibiting hyperglycemia, but not hyperinsulinemia, with mild left ventricular dysfunction. Employing 3-D electron microscopy (SBF-SEM) we determined that compared to wild-type, WT, the GENA348 subsarcolemma mitochondria (SSM) are ~ 2-fold larger, consistent with up-regulation of fusion proteins Mfn1, Mfn2 and Opa1. Further, in comparison, GENA348 mitochondria are more irregular in shape, have more tubular projections with SSM projections being longer and wider. Mitochondrial density is also increased in the GENA348 myocardium consistent with up-regulation of PGC1-α and stalled mitophagy (down-regulation of PINK1, Parkin and Miro1). GENA348 mitochondria have more irregular cristae arrangements but cristae dimensions and density are similar to WT. GENA348 Complex activity (I, II, IV, V) activity is decreased but the OCR is increased, potentially linked to a shift towards fatty acid oxidation due to impaired glycolysis. These novel data reveal that dysregulated mitochondrial morphology, dynamics and function develop in the early stages of diabetes.https://doi.org/10.1038/s41598-022-04929-1 |
| spellingShingle | Bodour S. Rajab Sarah Kassab Connor D. Stonall Hussam Daghistani Stephen Gibbons Mamas Mamas David Smith Aleksandr Mironov Zainab AlBalawi Yin Hua Zhang Florence Baudoin Min Zi Sukhpal Prehar Elizabeth J. Cartwright Ashraf Kitmitto Differential remodelling of mitochondrial subpopulations and mitochondrial dysfunction are a feature of early stage diabetes Scientific Reports |
| title | Differential remodelling of mitochondrial subpopulations and mitochondrial dysfunction are a feature of early stage diabetes |
| title_full | Differential remodelling of mitochondrial subpopulations and mitochondrial dysfunction are a feature of early stage diabetes |
| title_fullStr | Differential remodelling of mitochondrial subpopulations and mitochondrial dysfunction are a feature of early stage diabetes |
| title_full_unstemmed | Differential remodelling of mitochondrial subpopulations and mitochondrial dysfunction are a feature of early stage diabetes |
| title_short | Differential remodelling of mitochondrial subpopulations and mitochondrial dysfunction are a feature of early stage diabetes |
| title_sort | differential remodelling of mitochondrial subpopulations and mitochondrial dysfunction are a feature of early stage diabetes |
| url | https://doi.org/10.1038/s41598-022-04929-1 |
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