Nuclear Genome-Encoded Long Noncoding RNAs and Mitochondrial Damage in Diabetic Retinopathy.

Ghulam Mohammad,Renu A Kowluru

doi:10.3390/cells10123271

Ghulam Mohammad, Renu A Kowluru

Open Access

https://doi.org/10.3390/cells10123271

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Journal: Cells	Publication Date: Nov 23, 2021
Citations: 20	License type: CC BY 4.0

Affiliation: Wayne State University, Kresge Eye Institute

Abstract

Retinal mitochondria are damaged in diabetes-accelerating apoptosis of capillary cells, and ultimately, leading to degenerative capillaries. Diabetes also upregulates many long noncoding RNAs (LncRNAs), including LncMALAT1 and LncNEAT1. These RNAs have more than 200 nucleotides and no open reading frame for translation. LncMALAT1 and LncNEAT1 are encoded by nuclear genome, but nuclear-encoded LncRNAs can also translocate in the mitochondria. Our aim was to investigate the role of LncMALAT1 and LncNEAT1 in mitochondrial homeostasis. Using human retinal endothelial cells, the effect of high glucose on LncMALAT1 and LncNEAT1 mitochondrial localization was examined by RNA fluorescence in situ hybridization. The role of these LncRNAs in mitochondrial membrane potential (by JC-I staining), mtDNA integrity (by extended length PCR) and in protective mtDNA nucleoids (by SYBR green staining) was examined in MALAT1- or NEAT1-siRNA transfected cells. High glucose increased LncMALAT1 and LncNEAT1 mitochondrial expression, and MALAT1-siRNA or NEAT1-siRNA ameliorated glucose-induced damage to mitochondrial membrane potential and mtDNA, and prevented decrease in mtDNA nucleoids. Thus, increased mitochondrial translocation of LncMALAT1 or LncNEAT1 in a hyperglycemic milieu plays a major role in damaging the mitochondrial structural and genomic integrity. Regulation of these LncRNAs can protect mitochondrial homeostasis, and ameliorate formation of degenerative capillaries in diabetic retinopathy.

Highlights

Diabetes is one of the fastest growing health challenges of the 21st century, and~80% of patients develop retinopathy after 15 years of diabetes; worldwide, 17 million people have proliferative diabetic retinopathy
Regulation of almost every stage of gene expression is mediated by long noncoding RNAs (LncRNAs), the noncoding RNAs with over 200 nucleotides and higher tissue specificity compared to miRNAs [36]
Most of the LncRNAs function outside the mitochondria, several nuclear genome-encoded LncRNAs are found in the mitochondria, and are implicated in mitochondrial function and dynamics [37,38,39]

Summary

Introduction

Diabetes is one of the fastest growing health challenges of the 21st century, and~80% of patients develop retinopathy after 15 years of diabetes; worldwide, 17 million people have proliferative diabetic retinopathy. Evolving research has shown that only one-fifth of the transcription across the human genome is associated with protein-coding genes, and the non-protein-coding portion of the human genome is ~4 times more than the coding RNA sequences. LncRNAs are a large and heterogeneous group of functional RNAs that are mainly encoded by nuclear DNA, and are shown to play crucial roles in the regulation of pathophysiological processes in many chronic diseases including cancer, diabetes and its complications [7,8,9,10,11].

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