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Mitochondrial Fragmentation and Long Noncoding RNA MALAT1 in Diabetic Retinopathy
1Ophthalmology, Visual and Anatomical Sciences, Kresge Eye Institute, Wayne State University, Detroit, MI 48201, USA.
Abstract:
Mitochondria are dynamic in nature and depending on the energy demand they fuse and divide. This fusion-fission process is impaired in diabetic retinopathy and the promoter DNA of Mfn2, a fusion gene, is hypermethylated and its expression is downregulated. Long noncoding RNAs (RNAs with >200 nucleotides that do not encode proteins) can regulate gene expression by interacting with DNA, RNA, and proteins. Several LncRNAs are aberrantly expressed in diabetes, and among them, MALAT1 is upregulated in the retina, altering the expression of the genes associated with inflammation. Our aim was to investigate MALAT1's role in mitochondrial dynamics in diabetic retinopathy. Using MALAT1-siRNA-transfected human retinal endothelial cells (HRECs) and human retinal Muller cells (RMCs) incubated in 20 mM D-glucose, Mfn2 expression and activity and its promoter DNA methylation were quantified. Mitochondrial integrity was evaluated by analyzing their fragmentation, ultrastructure, membrane potential, and oxygen consumption rate. Compared to normal glucose, high glucose upregulated MALAT1 expression and downregulated Mfn2 expression and activity in both HRECs and RMCs. MALAT1-siRNA ameliorated the glucose-induced increase in Mfn2 promoter DNA hypermethylation and its activity. MALAT1-siRNA also protected against mitochondrial fragmentation, structural damage, and reductions in the oxygen consumption rate. In conclusion, the upregulation of MALAT1 in diabetes facilitates Mfn2 promoter DNA hypermethylation in retinal vascular and nonvascular cells, leading to its suppression and the accumulation of the fragmented/damaged mitochondria. Thus, the regulation of MALAT1 has the potential to protect mitochondria and provide a possible new target to inhibit/prevent the blinding disease in diabetic patients.
Insights
High glucose in diabetic retinopathy upregulates MALAT1, causing Mfn2 gene hypermethylation and mitochondrial damage. Inhibiting MALAT1 protects mitochondria and may prevent diabetic blindness.
Area of Science:
- Mitochondrial dynamics
- Epigenetics
- Diabetic retinopathy
Background:
- Mitochondrial fusion-fission is crucial for cellular energy and impaired in diabetic retinopathy.
- The fusion gene Mfn2 shows hypermethylated promoter DNA and reduced expression in this condition.
- Long noncoding RNAs (LncRNAs) like MALAT1 are implicated in diabetes-related inflammation and gene expression.
Purpose of the Study:
- To investigate the role of MALAT1 in mitochondrial dynamics within diabetic retinopathy.
- To determine if MALAT1 influences Mfn2 expression and mitochondrial integrity under high glucose conditions.
Main Methods:
- Human retinal endothelial cells (HRECs) and Muller cells (RMCs) were transfected with MALAT1-siRNA and exposed to high glucose.
- Mfn2 expression, activity, and promoter DNA methylation were quantified.
- Mitochondrial integrity was assessed via fragmentation, ultrastructure, membrane potential, and oxygen consumption.
Main Results:
- High glucose upregulated MALAT1 and downregulated Mfn2 expression and activity in HRECs and RMCs.
- MALAT1-siRNA transfection reversed high glucose-induced Mfn2 promoter hypermethylation and restored Mfn2 activity.
- MALAT1-siRNA protected cells against mitochondrial fragmentation, structural damage, and reduced oxygen consumption.
Conclusions:
- Upregulated MALAT1 in diabetes promotes Mfn2 promoter hypermethylation in retinal cells, suppressing Mfn2 and damaging mitochondria.
- Targeting MALAT1 offers a potential therapeutic strategy to protect mitochondria and prevent vision loss in diabetic retinopathy.
