Mitochondrial DNA copy number in adults with and without Type 1 diabetes

Jenkins, Alicia J.; Carroll, Luke M.; Huang, Michael L.H.; Wen-Loh, Yik; Mangani, Abubakar; O'Neal, David N.; Januszewski, Andrzej S.

doi:10.1016/j.diabres.2023.110877

Cited by 4 publications

(2 citation statements)

References 48 publications

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“…In summary, we demonstrate several novel important measures of diabetic tissue damage in the heart, kidneys and skin in mouse models which are exacerbated by variation in the mitochondrial genome. Our results implicate mtDNA variation as a new genetic factor to investigate in human diabetes, adding to recent human studies showing associations between mt-DNA-CN with diabetes per se and chronic diabetes complications [16]. This presents a unique new model to further research into the pathogenesis, prevention and treatment of chronic diabetes complications that are a cause of major morbidity and premature mortality.…”

Section: Discussionsupporting

confidence: 58%

“…Mitochondria are key to addressing oxidative stress. In keeping with a key role of mitochondria number and/or function in diabetes and its outcomes, we recently reported lower mitochondrial DNA copy number (mtDNA-CN) in blood of adults with Type 1 diabetes relative to their non-diabetic peers, and in diabetic subjects with vs. without kidney damage [16], as noted in people with Type 2 diabetes [17]. Other studies demonstrated lower mtDNA-CN with increasing age and associations with health status [18].…”

Section: Introductionsupporting

confidence: 53%

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

Januszewski,

Blake,

Zhang

et al. 2024

Antioxidants

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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.

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Section: Discussionsupporting

confidence: 58%

Section: Introductionsupporting

confidence: 53%

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

Januszewski,

Blake,

Zhang

et al. 2024

Antioxidants

Self Cite

View full text Add to dashboard Cite

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Mitochondrial dysfunction in kidney stones and relief of kidney stones after reducing mtROS

Xu,

Li,

et al. 2024

Urolithiasis

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The fetal origins of metabolic health: exploring the association between newborn biological age and metabolism hormones in childhood

Jia,

Qiu,

et al. 2024

BMC Med

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Background Telomere length (TL), mitochondrial DNA copy number (mtDNAcn), and DNA methylation age (DNAmAge) are common aging biomarkers. However, research on the associations between these three markers at birth and subsequent metabolic status was limited. This study aimed to evaluate the association between TL, mtDNAcn, and DNAmAge in newborns and the variation in metabolic hormones of children at 3 years old. Methods This research involved 895 mother–child pairs from a birth cohort in China, with TL and mtDNAcn measured using quantitative real-time PCR, DNA methylation (DNAm) assessed using Infinium MethylationEPIC Beadchip, and DNAm age (DNAmAge) determined using Horvath’s epigenetic clock. Insulin and leptin levels were measured via electrochemiluminescence assay. Multivariable adjusted linear regression and restricted cubic spline (RCS) analysis were utilized to examine the association between aging markers and metabolic hormones. Results The linear regression analysis indicated the percentage change of metabolism hormones for per doubling of aging biomarkers alterations and found significant associations between DNAmAge and insulin levels (adjusted percent change (95% CI), − 13.22 (− 23.21 to − 1.94)), TL and leptin levels (adjusted percent change (95% CI), 15.32 (1.32 to 31.24)), and mtDNAcn and leptin levels (adjusted percent change (95% CI), − 14.13 (− 21.59 to − 5.95)). The RCS analysis revealed significant non-linear associations between TL (Ln transformed) and insulin (Ln transformed) ( P = 0.024 for nonlinearity), as well as DNAmAge (Ln transformed) and leptin (Ln transformed) ( P = 0.043 for nonlinearity). Specifically, for TL and insulin, a positive association was observed when TL (Ln transformed) was less than − 0.05, which transitioned to an inverse association when TL (Ln transformed) was greater than − 0.05. Regarding DNAmAge and leptin, there was a sharp decline when DNAmAge (Ln transformed) was less than − 1.35, followed by a plateau between − 1.35 and − 0.67 and then a further decline when DNAmAge (Ln transformed) was greater than − 0.67. Conclusions In this prospective birth cohort study, variation in metabolic hormones of children at 3 years old was associated with TL, mtDNAcn, and DNAmAge at birth. These findings suggested that TL, mtDNAcn, and DNAmAge might play a role in the biological programming of metabolic health from birth. Supplementary Information The online version contains supplementary material available at 10.1186/s12916-024-03629-z.

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Mitochondrial DNA copy number in adults with and without Type 1 diabetes

Cited by 4 publications

References 48 publications

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

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

Mitochondrial dysfunction in kidney stones and relief of kidney stones after reducing mtROS

The fetal origins of metabolic health: exploring the association between newborn biological age and metabolism hormones in childhood

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