Intracellular Iron Metabolism

In the absence of a demonstrable yeast iron-storage protein (ferritin), we have to recognize that, despite our substantial advances in understanding iron uptake in yeast, we know practically nothing about intracellular iron metabolism - except that is for iron transport into, and out of, mitochondria.

Intracellular Iron Metabolism 4*4*1 Mitochondrial Iron Transport

As we will see in Chapter 7, the mitochondria are not only the energy powerhouse of the cell, they is also the site of both haem (Lange etal., 1999) and iron-sulfur cluster (Lill et al., 1999) biosynthesis. The proteins that contain haem and iron-sulfur clusters are not all located in the mitochondria, which makes the mitochondria a focal point of intracellular iron metabolism. We recognize that mitochondrial iron transport must occur, although we do not quite know how it functions, but from recent work it seems that there must be a mitochondrial iron cycle (Radisky et al., 1999), such that mitochondria not only import iron but also export it. Analysis of the function of the gene YFH1 (Babcock et al., 1997), which is a homologue of the mammalian gene Frataxin (mutated in Friedrich's ataxia), shows that is involved in mitochondrial iron efflux. Yfh1p is a protein of 125 amino acids localized in the matrix of the mitochondria. The phenotypes of strains in which YFH1 has been deleted reflect respiratory incompetence and decreased cytosolic iron, which are the result of mitochondrial iron accumulation. The excedent of mitochondrial iron produces increased amounts of hydroxyl radical which in turn damages mitochondrial proteins, lipids and DNA.11 The damage to mitochondrial DNA generates respiratory incompetent yeast, termed petites, which can survive because they regenerate cytosolic NADH by fermentation. Although the ATP yield is much less than by respiration (about twentyfold), their survival strategy lies in what Louis Pasteur described as 'la vie sans air' (life without air). The petite mutants should in fact have a selective advantage because they no longer produce toxic reactive oxygen species at the mitochondrial inner membrane. It has been established that Yfh1p mediates iron efflux from mitochondria (Radisky et al., 1999), yet it is located in the matrix and has no transmembrane domain. It may function either by regulating iron transport, or by keeping iron in a form that is recognized by an as yet to be discovered transport protein. Transcription of YFH1 is not iron regulated.

Although iron-sulfur proteins are found in various cellular localizations in eukaryotic cells, mitochondria are the major site of Fe-S cluster biosynthesis (Lill et al., 1999). Deletions in nuclear genes involved in mitochondrial iron-sulfur cluster formation lead to massive accumulation of iron in mitochondria (Chapter 7). For example, deletion of ATM1, a mitochondrial ATPase, which seems to be responsible for the export of Fe-S clusters, leads to respiratory incompetence, excessive iron accumulation and leucine auxotrophy (Kispal et al., 1999). In Ayfh1 cells there is only partial loss of mitochondrial Fe-S enzymes and the cells are not leucine auxotrophs.

" This constitutes what is often termed the oxygen paradox. The symbiotic cohabitation of a prokaryotic cell within a eukaryotic host enabled the mitochondrial respiratory chain to produce much more ATP than could be achieved by fermentation: two ATP molecules are produced by homolactic fermentation (e.g. in muscle) or by alcoholic fermentation (e.g. in yeast) per molecule of glucose, whereas the combined operation of shuttles for transferring electrons from cytoplasmic NADH to mitochondria, transfer of pyruvate into the mitochondrial matrix and its conversion to acetyl CoA, the citric-acid cycle together with the mitochondrial electron transport chain and its associated ATP synthase raises this figure to 36-38 ATP molecules per molecule of glucose. However there is a price to be paid. The transfer of electrons along the respiratory chain generates reactive oxygen species, notably the hydroxyl radical which can provoke oxidative damage. This is the essence of the paradox - dioxygen is both beneficial yet at the same time potentially toxic. More on this subject in Chapter 10.

It thus seems unlikely thatYfh1p plays a role in either Fe-S cluster formation or their export.

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