Increased Diabetes Complications in a Mouse Model of Oxidative Stress Due to ‘Mismatched’ Mitochondrial DNA

Author:

Januszewski Andrzej S.123,Blake Rachel45,Zhang Michael1,Ma Ben1,Anand Sushma45,Pinkert Carl A.6ORCID,Kelly Darren J.1,Jenkins Alicia J.127,Trounce Ian A.145ORCID

Affiliation:

1. Department of Medicine, St. Vincent’s Hospital, University of Melbourne, Fitzroy, VIC 3065, Australia

2. NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW 2006, Australia

3. Sydney Pharmacy School, The University of Sydney, Sydney, NSW 2006, Australia

4. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, VIC 3002, Australia

5. Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC 3000, Australia

6. Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA

7. Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia

Abstract

Associations between chronic diabetes complications and mitochondrial dysfunction represent a subject of major importance, given the diabetes pandemic and high personal and socioeconomic costs of diabetes and its complications. Modelling diabetes complications in inbred laboratory animals is challenging due to incomplete recapitulation of human features, but offer mechanistic insights and preclinical testing. As mitochondrial-based oxidative stress is implicated in human diabetic complications, herein we evaluate diabetes in a unique mouse model that harbors a mitochondrial DNA from a divergent mouse species (the ‘xenomitochondrial mouse’), which has mild mitochondrial dysfunction and increased oxidative stress. We use the streptozotocin-induced diabetes model with insulin supplementation, with 20-weeks diabetes. We compare C57BL/6 mice and the ‘xenomitochondrial’ mouse, with measures of heart and kidney function, histology, and skin oxidative stress markers. Compared to C57BL/6 mice, the xenomitochondrial mouse has increased diabetic heart and kidney damage, with cardiac dysfunction, and increased cardiac and renal fibrosis. Our results show that mitochondrial oxidative stress consequent to divergent mtDNA can worsen diabetes complications. This has implications for novel therapeutics to counter diabetes complications, and for genetic studies of risk, as mtDNA genotypes may contribute to clinical outcomes.

Funder

Juvenile Diabetes Research Foundation

Publisher

MDPI AG

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