The effect of mitochondrial dysfunction on cytosolic nucleotide metabolism - PubMed (original) (raw)

The effect of mitochondrial dysfunction on cytosolic nucleotide metabolism

Claus Desler et al. J Nucleic Acids. 2010.

Abstract

Several enzymes of the metabolic pathways responsible for metabolism of cytosolic ribonucleotides and deoxyribonucleotides are located in mitochondria. Studies described in this paper suggest dysfunction of the mitochondria to affect these metabolic pathways and limit the available levels of cytosolic ribonucleotides and deoxyribonucleotides, which in turn can result in aberrant RNA and DNA synthesis. Mitochondrial dysfunction has been linked to genomic instability, and it is possible that the limiting effect of mitochondrial dysfunction on the levels of nucleotides and resulting aberrant RNA and DNA synthesis in part can be responsible for this link. This paper summarizes the parts of the metabolic pathways responsible for nucleotide metabolism that can be affected by mitochondrial dysfunction.

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Figures

Figure 1

Figure 1

Overview of metabolic pathways responsible for nucleotide metabolism that can be affected by mitochondrial dysfunction. The illustration depicts the outer and inner mitochondrial membrane. Complexes of the electron transport chain are illustrated with boxes marked with numerals I-IV. Boxes marked with V depict ATP synthase. Darkened boxes illustrate enzymes of interest. Upper left: Dihydroorotate (DHODHase) is an integral enzyme in the de novo synthesis of pyrimidines. The enzyme is located in the inner mitochondrial membrane and its activity is dependent on an active electron transport chain. Upper right: Mitochondrial nitric oxide synthase (mtNOS) creates NO in a Ca2+ dependent reaction. The enzyme is located in the inner mitochondrial membrane where it interacts with both complexes I and IV of the electron transport chain. The activity of mtNOS is linked to the mitochondrial membrane potential. NO has the potential to inhibit the activity of Complexes I, III, and IV, but also ribonucleotide reductase in the cytosol. Lower: Illustration of the mitochondrial production of one-carbon units and mitochondrial export of formate. See text for details.

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