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Mitochondria-Targeted Small Peptide, SS31 Ameliorates Diabetes Induced Mitochondrial Dynamics in Male TallyHO/JngJ Mice

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Abstract

The escalating burden of type 2 diabetes (T2D) and its related complications has become a major public health challenge worldwide. Substantial evidence indicates that T2D is one of the culprits for the high prevalence of Alzheimer’s disease (AD) in diabetic subjects. This study aimed to investigate the possible mitochondrial alterations in the pancreas induced by hyperglycemia in diabetes. We used a diabetic TallyHO/JngJ (TH) and non-diabetic, SWR/J mice strains. The diabetic and non-diabetic status in animals was assessed by performing intraperitoneal glucose tolerance test at four time points, i.e., 4, 8, 16, and 24 weeks of age. We divided 24-week-old TH and SWR/J mice into 3 groups: controls, diabetic TH mice, and diabetic TH mice treated with SS31 peptide. After the treatment of male TH mice with SS31, intraperitoneally, for 4 weeks, we studied mitochondrial dynamics, biogenesis, and function. The mRNA and protein expression levels of mitochondrial proteins were evaluated using qPCR and immunoblot analysis. The diabetic mice after 24 weeks of age showed overt pancreatic injury as demonstrated by disintegration and atrophy of β cells with vacuolization and reduced islet size. Mitochondrial dysfunction was observed in TH mice, as evidenced by significantly elevated H2O2 production, lipid peroxidation, and reduced ATP production. Furthermore, mRNA expression and immunoblot analysis of mitochondrial dynamics genes were significantly affected in diabetic mice, compared with controls. However, treatment of animals with SS31 reduced mitochondrial dysfunction and restored most of the mitochondrial functions and mitochondrial dynamics processes to near normal in TH mice. In conclusion, mitochondrial dysfunction is established as one of the molecular events that occur in the pathophysiology of T2D. Further, SS31 treatment may confer protection against the mitochondrial alterations induced by hyperglycemia in diabetic TallyHO/JngJ mice.

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The research presented in this article was supported by NIH grants AG042178, AG047812, NS105473, AG060767, AG069333, and AG066347 (to PHR). JSB was financially supported by the University Grants Commission, Govt. of India, under Raman Postdoctoral Fellowship in the USA  [F.No.5-82/2016 (IC)].

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Authors and Affiliations

  1. Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India

    Jasvinder Singh Bhatti

  2. Department of Biotechnology, Sri Guru Gobind Singh College, Chandigarh, India

    Jasvinder Singh Bhatti

  3. Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX, 79430, USA

    Jasvinder Singh Bhatti, Kavya Thamarai, Ramesh Kandimalla, Maria Manczak, Xiangling Yin & P. Hemachandra Reddy

  4. Department of Biochemistry, Kakatiya Medical College, Warangal, Telangana, 506007, India

    Ramesh Kandimalla

  5. Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad, Telangana, 500007, India

    Ramesh Kandimalla

  6. Internal Medicine Department, Texas Tech University Health Sciences Center, 3601 4th Street / 4B 207, MS 9424, Lubbock, TX, 79430, USA

    Subodh Kumar, Murali Vijayan & P. Hemachandra Reddy

  7. Cell Biology & Biochemistry Department, Texas Tech University Health Sciences Center, 3601 4th Street / 4B 207, MS 9424, Lubbock, TX, 79430, USA

    P. Hemachandra Reddy

  8. Pharmacology & Neuroscience Department, Texas Tech University Health Sciences Center, 3601 4th Street / 4B 207, MS 9424, Lubbock, TX, 79430, USA

    P. Hemachandra Reddy

  9. Neurology and Public Health Departments, Texas Tech University Health Sciences Center, 3601 4th Street / 4B 207, MS 9424, Lubbock, TX, 79430, USA

    P. Hemachandra Reddy

  10. Speech, Language and Hearing Sciences Departments, Texas Tech University Health Sciences Center, 3601 4th Street / 4B 207, MS 9424, Lubbock, TX, 79430, USA

    P. Hemachandra Reddy

Authors
  1. Jasvinder Singh Bhatti
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  2. Kavya Thamarai
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  3. Ramesh Kandimalla
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  4. Maria Manczak
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  5. Xiangling Yin
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  6. Subodh Kumar
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  7. Murali Vijayan
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  8. P. Hemachandra Reddy
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Corresponding author

Correspondence to P. Hemachandra Reddy.

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Bhatti, J.S., Thamarai, K., Kandimalla, R. et al. Mitochondria-Targeted Small Peptide, SS31 Ameliorates Diabetes Induced Mitochondrial Dynamics in Male TallyHO/JngJ Mice. Mol Neurobiol 58, 795–808 (2021). https://doi.org/10.1007/s12035-020-02142-7

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