Gene Expression Pattern in Transmitochondrial Cytoplasmic Hybrid Cells Harboring Type 2 Diabetes-Associated Mitochondrial DNA Haplogroups

Abstract

Decreased mitochondrial function plays a pivotal role in the pathogenesis of type 2 diabetes mellitus (T2DM). Recently, it was reported that mitochondrial DNA (mtDNA) haplogroups confer genetic susceptibility to T2DM in Koreans and Japanese. Particularly, mtDNA haplogroup N9a is associated with a decreased risk of T2DM, whereas haplogroups D5 and F are associated with an increased risk. To examine functional consequences of these haplogroups without being confounded by the heterogeneous nuclear genomic backgrounds of different subjects, we constructed transmitochondrial cytoplasmic hybrid (cybrid) cells harboring each of the three haplogroups (N9a, D5, and F) in a background of a shared nuclear genome. We compared the functional consequences of the three haplogroups using cell-based assays and gene expression microarrays. Cell-based assays did not detect differences in mitochondrial functions among the haplogroups in terms of ATP generation, reactive oxygen species production, mitochondrial membrane potential, and cellular dehydrogenase activity. However, differential expression and clustering analyses of microarray data revealed that the three haplogroups exhibit a distinctive nuclear gene expression pattern that correlates with their susceptibility to T2DM. Pathway analysis of microarray data identified several differentially regulated metabolic pathways. Notably, compared to the T2DM-resistant haplogroup N9a, the T2DM-susceptible haplogroup F showed down-regulation of oxidative phosphorylation and up-regulation of glycolysis. These results suggest that variations in mtDNA can affect the expression of nuclear genes regulating mitochondrial functions or cellular energetics. Given that impaired mitochondrial function caused by T2DM-associated mtDNA haplogroups is compensated by the nuclear genome, we speculate that defective nuclear compensation, under certain circumstances, might lead to the development of T2DM.

Severe Septic Patients with Mitochondrial DNA Haplogroup JT Show Higher Survival Rates: A Prospective, Multicenter, Observational Study

“…MtDNA genetic variation can alter the expression of nuclear genes [19]. Cybrids are cell lines that share the nuclear genetic background and culture conditions and only differ in the mtDNA genotype.…”

PARK2 variability in Polish Parkinson’s disease patients - interaction with mitochondrial haplogroups

“…On the other hand, functional studies could contribute to better understanding of PARK2 , TFAM and mtDNA variation interplay and their involvement in PD pathogenesis. Recent findings in cybrid models demonstrated that mitochondrial haplogroups influenced mtDNA replication and transcription, and mitochondrial and nuclear genes expression pattern, involved in oxidative phosphorylation pathway [29,30]. Mitochondrial parameters were also changed in fibroblasts and leukocytes derived from EOPD patients carrying PARK2 mutations [8,9].…”

Generation and Bioenergetic Profiles of Cybrids with East Asian mtDNA Haplogroups

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