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Dissecting the roles of the nuclear and mitochondrial genomes in a mouse model of autoimmune diabetes

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posted on 2023-10-17, 21:12 authored by Weiwei Zou, Janaki Chezhian, Tenghui Yu, Wensheng Liu, Jimmy Vu, Jesse Slone, Taosheng Huang

Abstract

Mitochondria, the organelles responsible for generating ATP in eukaryotic cells, have been previously implicated as a contributor to diabetes. However, mitochondrial proteins are encoded by both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). In order to better understand the relative contribution of each of these genomes to diabetes, a chimeric mitochondrial-nuclear exchange (MNX) mouse was created via pronuclear transfer carrying nDNA from a strain susceptible to type 1 diabetes (NOD/ShiLtJ) and mtDNA from non-diabetic C57BL/6J mice. Inheritance of the resulting “heteroplasmic” mtDNA mixture was then tracked across multiple generations, showing that offspring heteroplasmy generally followed that of the mother, with occasional large shifts consistent with an mtDNA “bottleneck” in the germline. In addition, the survival and incidence of diabetes for MNX mice was tracked and compared to unaltered NOD/ShiLtJ control mice. The results indicate improved survival and a delay in diabetes onset in the MNX mice, demonstrating that the mtDNA holds a critical influence on the disease phenotype. Finally, enzyme activity assays showed that the NOD/ShiLtJ mice have a significant hyperactivity of complex I of the ETC relative to MNX mice, suggesting that a particular mtDNA variant (m.9461T>C) may be responsible for the disease causation in the original NOD/ShiLtJ strain.


Article Highlights

· Mitochondria have been previously implicated in diabetes, but the specific genetic factors remain unclear.

· To better understand the contributions of mitochondrial genes in the nuclear DNA (nDNA) versus the mitochondrial DNA (mtDNA), we created Mitochondrial-Nuclear Exchange (MNX) mice carrying nDNA from a diabetic strain and mtDNA from non-diabetic mice.

· Longterm tracking of MNX mice shows occasional large shifts in heteroplasmy consistent with an mtDNA bottleneck in the germline.

· In addition, the MNX mice showed improved survival and delayed incidence of diabetes relative to the unaltered diabetic mice, which appears to be linked to the activity of respiratory complex I.

Funding

Key R&D Program of China x 2021YFC2700901

Ministry of Science and Technology of the People's Republic of China > National Natural Science Foundation of China 82001635 U20A20350

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