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Differential remodelling of mitochondrial subpopulations and mitochondrial dysfunction are a feature of early stage diabetes

Authors
  • Rajab, Bodour S.1, 2
  • Kassab, Sarah1
  • Stonall, Connor D.1
  • Daghistani, Hussam1, 3
  • Gibbons, Stephen1
  • Mamas, Mamas1, 4
  • Smith, David5
  • Mironov, Aleksandr5
  • AlBalawi, Zainab1
  • Zhang, Yin Hua1, 6, 7
  • Baudoin, Florence1
  • Zi, Min1
  • Prehar, Sukhpal1
  • Cartwright, Elizabeth J.1
  • Kitmitto, Ashraf1
  • 1 The University of Manchester, Manchester Academic Health Science Centre, AV Hill, Dover Street, Manchester, M13 9PL, UK , Manchester (United Kingdom)
  • 2 Umm Al-Qura University, Mecca, Saudi Arabia , Mecca (Saudi Arabia)
  • 3 King Abdulaziz University, Jeddah, Saudi Arabia , Jeddah (Saudi Arabia)
  • 4 Keele University, Stoke-on-Trent, UK , Stoke-on-Trent (United Kingdom)
  • 5 The University of Manchester, Manchester, UK , Manchester (United Kingdom)
  • 6 Seoul National University, College of Medicine, Seoul, Korea , Seoul (South Korea)
  • 7 Yanbian University Hospital, Jilin, China , Jilin (China)
Type
Published Article
Journal
Scientific Reports
Publisher
Springer Nature
Publication Date
Jan 19, 2022
Volume
12
Issue
1
Identifiers
DOI: 10.1038/s41598-022-04929-1
Source
Springer Nature
Disciplines
  • article
License
Green

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.

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