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African and Asian Mitochondrial DNA Haplogroups Confer Resistance Against Diabetic Stresses on Retinal Pigment Epithelial Cybrid Cells In Vitro.

ABSTRACT: Diabetic retinopathy (DR) is the most common cause of blindness for individuals under the age of 65. This loss of vision can be due to ischemia, neovascularization, and/or diabetic macular edema, which are caused by breakdown of the blood-retina barrier at the level of the retinal pigment epithelium (RPE) and inner retinal vasculature. The prevalence of diabetes and its complications differ between Caucasian-Americans and certain minority populations, such as African-Americans and Asian-Americans. Individuals can be classified by their mitochondrial haplogroups, which are collections of single nucleotide polymorphisms (SNPs) in mitochondrial DNA (mtDNA) representing ancient geographic origins of populations. In this study, we compared the responses of diabetic human RPE cybrids, cell lines containing identical nuclei but mitochondria from either European (maternal European) or maternal African or Asian individuals, to hypoxia and high glucose levels. The African and Asian diabetic ([Afr+Asi]/DM) cybrids showed (1) resistance to both hyperglycemic and hypoxic stresses; (2) downregulation of pro-apoptotic indicator BAX; (3) upregulation of DNA methylation genes, such as DNMT3A and DNMT3B; and (4) resistance to DNA demethylation by the methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-dC) compared to European diabetic (Euro/DM) cybrids. Our findings suggest that mitochondria from African and Asian diabetic subjects possess a "metabolic memory" that confers resistance against hyperglycemia, hypoxia, and demethylation, and that this "metabolic memory" can be transferred into the RPE cybrid cell lines in vitro.

SUBMITTER: Dolinko AH

PROVIDER: S-EPMC7123578 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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African and Asian Mitochondrial DNA Haplogroups Confer Resistance Against Diabetic Stresses on Retinal Pigment Epithelial Cybrid Cells In Vitro.

Dolinko Andrew H AH Chwa Marilyn M Atilano Shari R SR Kenney M Cristina MC

Molecular neurobiology 20191206 3

Diabetic retinopathy (DR) is the most common cause of blindness for individuals under the age of 65. This loss of vision can be due to ischemia, neovascularization, and/or diabetic macular edema, which are caused by breakdown of the blood-retina barrier at the level of the retinal pigment epithelium (RPE) and inner retinal vasculature. The prevalence of diabetes and its complications differ between Caucasian-Americans and certain minority populations, such as African-Americans and Asian-American ...[more]

PMID: 31811564

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Project description:BackgroundDrug therapy yields different results depending on its recipient population. Cisplatin, a commonly used chemotherapeutic agent, causes different levels of resistance and side effects for different patients, but the mechanism(s) are presently unknown. It has been assumed that this variation is a consequence of differences in nuclear (n) DNA, epigenetics, or some external factor(s). There is accumulating evidence that an individual's mitochondrial (mt) DNA may play a role in their response to medications. Variations within mtDNA can be observed, and an individual's mtDNA can be categorized into haplogroups that are defined by accumulations of single nucleotide polymorphisms (SNPs) representing different ethnic populations.MethodsThe present study was conducted on transmitochondrial cytoplasmic hybrids (cybrids) that possess different maternal-origin haplogroup mtDNA from African (L), Hispanic [A+B], or Asian (D) backgrounds. Cybrids were created by fusing Rho0 ARPE-19 cells (lacking mtDNA) with platelets, which contain numerous mitochondria but no nuclei. These cybrid cells were cultured to passage five, treated with cisplatin, incubated for 48 h, then analyzed for cell metabolic activity (tetrazolium dye (MTT) assay), mitochondrial membrane potential (JC-1 assay), cytotoxicity (lactate dehydrogenase (LDH) assay), and gene expression levels for ALK, BRCA1, EGFR, and ERBB2/HER2.ResultsResults indicated that untreated cybrids with varying mtDNA haplogroups had similar relative metabolic activity before cisplatin treatment. When treated with cisplatin, (1) the decline in metabolic activity was greatest in L (27.4%, p < 0.012) < D (24.86%, p = 0.0001) and [A+B] cybrids (24.67%, p = 0.0285) compared to untreated cybrids; (2) mitochondrial membrane potential remained unchanged in all cybrids (3) LDH production varied between cybrids (L >[A+B], p = 0.0270). (4) The expression levels decreased for ALK in L (p < 0.0001) and [A+B] (p = 0.0001) cybrids but not in D cybrids (p = 0.285); and decreased for EGFR in [A+B] cybrids (p = 0.0246) compared to untreated cybrids.ConclusionOur findings suggest that an individual's mtDNA background may be associated with variations in their response to cisplatin treatment, thereby affecting the efficiency and the severity of side effects from the treatment.

Dataset Information

African and Asian Mitochondrial DNA Haplogroups Confer Resistance Against Diabetic Stresses on Retinal Pigment Epithelial Cybrid Cells In Vitro.

Publications

African and Asian Mitochondrial DNA Haplogroups Confer Resistance Against Diabetic Stresses on Retinal Pigment Epithelial Cybrid Cells In Vitro.

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