Control of Mitochondrial Iron Metabolism by Products of the Iron-Sulfur Gene Complex

PI: Valeria Culotta and Laran Jensen
Johns Hopkins University

Background: A variety of enzymes contain iron-sulfur complexes that are critical for proper enzyme functioning and in some cases as regulatory switches. Examples of these enzymes are found in the tricarboxylic acid cycle, nitrogen fixation and other important biochemical reactions. The most thorough characterization of the formation and maintenance of these clusters has been done in bacteria. Other work in yeast found similar proteins. These investigators studied two yeast proteins, Isa1p and Isa2p, that are products of the iron-sulfur complex gene cluster and are responsible for mitochondrial iron metabolism and formation and repair of iron-sulfur centers.

Advance: To test the function of Isa1p and Isa2p, disruptions in the genes coding for the two proteins were performed. The resulting mutant yeast lived but were dependent on lysine and glutamate for growth and exhibited a respiratory deficiency due to the accumulation of mutations in the mitochodrial DNA. The mutants also had very high mitochondrial iron concentrations and the activities of the iron-sulfur containing enzymes aconitase and succinate dehydrogenase were significantly reduced.

Implication: These results provide evidence that Isa1p and Isa2p play important roles in iron metabolism and the formation and maintenance of iron-sulfur enzyme complexes. The high mitochondrial iron concentration seen in the mutants causes oxidative damage and is manifested in mitchondrial DNA mutations. Further understanding the metabolism of iron in mitochondria may have important implications for human diseases such as hemachromatosis and degenerative diseases associated with oxidative stress. [Area of Emphasis: New Approaches to Pathogenesis;

GPRA Goal: Add to the body of knowledge about normal and abnormal biological functions and behavior (Molecular and Cellular Mechanisms)]

Citation: Jensen LT, Culotta VC: Role of Saccharomyces cerevisiae ISA1 and ISA2 in iron homeostasis. Mol Cell Biol. 2011:3918-3927, 2000.