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Control of RNA oxidation as a novel mechanism for preventing mitochondrial dysfunction
Title
Control of RNA oxidation as a novel mechanism for preventing mitochondrial dysfunction.
Creator
Malla, Sulochan, Walker, Merritt, Graduate College, Li, Zhongwei
Abstract/Description
Mitochondria generate energy through oxidative phosphorylation in eukaryotic cell and produce large amount of reactive oxygen species ROS as byproducts during this process. In particular in mitochondria, oxidative modifications of biomolecules by ROS can cause their inactivation. The situation is exacerbated during oxidative stress when excessive amounts of ROS are produced. Oxidative damage of macromolecules causes mitochondrial dysfunction and eventually leads to numerous diseases such as...
Show moreMitochondria generate energy through oxidative phosphorylation in eukaryotic cell and produce large amount of reactive oxygen species ROS as byproducts during this process. In particular in mitochondria, oxidative modifications of biomolecules by ROS can cause their inactivation. The situation is exacerbated during oxidative stress when excessive amounts of ROS are produced. Oxidative damage of macromolecules causes mitochondrial dysfunction and eventually leads to numerous diseases such as cardiovascular and neural disorders. Although the deleterious effects of oxidized DNA, proteins and lipids have been extensively characterized, little is known about the potential causative effects of oxidized RNA. Here, we assessed RNA oxidation levels in the mitochondria and cytosol of cultured human cells, which was analyzed by using 8-hydroxyguanosine 8-oxo-G on the RNA as a marker for oxidative stress. Interestingly, our result revealed that 8-oxo-G levels of mitochondrial mt-RNA was relatively higher than that of cytosolic RNA suggesting that RNA is one of the contributing factors leading to mitochondrial dysfunction. To further evaluate the consequence of RNA oxidation, we will examine mitochondrial functionality, permeability, and cell viability to determine a correlation with the levels of 8-oxo-G in mt-RNA. We previously showed that human polynucleotide phosphorylase hPNPase, which mainly localizes to mitochondria and binds oxidized RNA with high affinity, reduces RNA oxidation and protects HeLa cell during oxidative stress. We intend to elucidate the potential role of hPNPase and its associated RNA helicase, hSUV3, in reducing mt-RNA oxidation which is of relevance to diseases associated with mitochondrial dysfunction.
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Date Issued
2014
PURL
http://purl.flvc.org/fau/fd/FA00005156
Format
Document (PDF)
Unraveling the molecular mechanism of human polynucleotide phosphorylase (hPNPase) in controlling oxidized RNA
Title
Unraveling the molecular mechanism of human polynucleotide phosphorylase (hPNPase) in controlling oxidized RNA.
Creator
Malla, Sulochan, Li, Zhongwei, Florida Atlantic University, Department of Biomedical Science, Charles E. Schmidt College of Science
Abstract/Description
Oxidation by reactive oxygen species is the major source of RNA damaging insult in living organisms. Increased RNA oxidation has been strongly implicated in a wide range of human diseases; predominantly neurodegeneration. Oxidized RNA should be removed from the cellular system to prevent their deleterious effect to the cells and organisms. In eukaryotic cells, mitochondria are the major intracellular sources of ROS and may cause greater damage to the mitochondrial RNA. In this study, we first...
Show moreOxidation by reactive oxygen species is the major source of RNA damaging insult in living organisms. Increased RNA oxidation has been strongly implicated in a wide range of human diseases; predominantly neurodegeneration. Oxidized RNA should be removed from the cellular system to prevent their deleterious effect to the cells and organisms. In eukaryotic cells, mitochondria are the major intracellular sources of ROS and may cause greater damage to the mitochondrial RNA. In this study, we first investigated the RNA oxidation, by measuring the level of 8-hydroxy-Guanosine (8-oxo-Guo), inside mitochondria and cytoplasm in cultured human cells. We discovered that the mitochondrial 8-oxo-Guo is higher than its cytoplasmic counterparts under both normal growth and oxidative stress condition. Next, we explored the role of human polynucleotide phosphorylase (hPNPase) in controlling RNA oxidation inside mitochondria and cytoplasm. hPNPase binds to oxidized RNA with higher affinity, reduces the 8-oxo-Guo level in total RNA and protects cells against oxidative stress. In this study, the molecular mechanism of hPNPase in 8-oxo-Guo reduction was investigated. First, the effect of hPNPase activities on the 8-oxo-Guo level in mitochondria and cytoplasm was examined. The knockdown of hPNPase increased both the mitochondrial and cytoplasmic 8-oxo-Guo, whereas overexpression had the opposite effect. Second, our study revealed that hSUV3, an RNA helicase that forms a functional complex with hPNPase in mitochondria, was dispensable in reducing 8-oxo-Guo levels.
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Date Issued
2019
PURL
http://purl.flvc.org/fau/fd/FA00013392
Subject Headings
RNA, Reactive Oxygen Species, Mitochondria, Oxidative stress
Format
Document (PDF)