Pathophysiology

Heme biosynthesis involves eight enzymes, four of which are cytoplasmic and four of which are localized in the mitochondria.

There are two distinct types of ¿-aminolevulinic acid synthase (ALA-S): ALA-S1 (housekeeping form) occurs in nonerythroid cells and its gene maps on the auto-some, and ALA-S2 (erythroid-specific form) occurs in erythroid cells and its gene maps on the X chromosome. Distinct aspects of heme synthesis regulation in non-erythroid and erythroid cells are related to the differences between these two ALA-S enzymes. In nonerythroid cells, the synthesis and activity of ALA-S1 is subject to feedback inhibition by heme, thus making ALA-S1 the rate-limiting enzyme for the heme pathway. In erythroid cells, heme does not inhibit either the activity or the synthesis of ALA-S2, but it does inhibit cellular iron uptake from transferrin without affecting its utilization for heme synthesis.

Table 6-25 shows the distinct features of iron and heme metabolism in erythroid and nonerythroid cells. These differences explain the large amount of heme production by erythroid cells compared to the low amount produced by non-erythroid cells. They also explain the mitochondrial deposition of iron in iron-loaded erythroid precursors.

Sideroblastic anemias result from injury to the mitochondria. Defects attributed to the mitochondrial pathways of heme synthesis result in sideroblastic anemias. Mitochondrial injury results from:

• Defective heme synthesis and the accumulation of iron, especially in erythroid precursors. This iron accumulation causes oxidative damage to the mitochondrial machinery through a Fenton reaction (i.e., the formation of a hydroxyl radical catalyzed by iron and reactive oxygen species damaging mitochondrial DNAby cross-linking DNA strands or by promoting the formation of DNA protein cross links).

• Congenital deletions of mitochondrial DNA.

Table 6-25. Iron and Heme Metabolism: Distinct Features in Erythroid Cells

Erythroid

Nonerythroid*

Iron

Iron Source Tf receptors

Regulation

Effect of heme on FE uptake from Tf Fe overload

Heme

Content Major function Control of Synthesis Effect of ALA-S

Heme Oxygenase

Exclusivity Tf Differentiation T Proliferation T Differentiation 4 Little change Transcriptional Inhibits Mitochondria

Non Covalent assoc.

with globin Very high O2 transport Fe from Tf Translational induction by Fe (IRE in 5' UTR) mRNA4 during erythroid differentiation

Primary mRNA stability No Effect

Cytosol ferritin (never mitochondria) Covalent binding to cytochromes Trace e- transport ALA-S

Feedback repression by heme (no IRE)

Induced by heme

'"Nonerythroid" cells, in this context, are represented by transformed cells grown in tissue cultures and hepatocytes; it is possible that some specialized cells (eg, macrophages) have other specific iron/heme metabolism characteristics.

Abbreviation: Tf, transferrin; ALA-S, aminolevulinic acid Synthase; IRE, iron-responsive element; 5'UTR, 5' untranslated region.

From Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanism in erythroid cells. Blood 1997;89:1-25, with permission.

Toxins or drugs responsible for causing sideroblastic anemia should be eliminated. Oral pyridoxine is used in some patients with either congenital or acquired sideroblastic anemia with partial response.

As a result of mitochondrial damage, there is increased deposition of iron in heme-containing cells (e.g., erythroid cells). Additionally, there is decreased oxidative phosphorylation and decreased adenosine triphosphate (ATP) synthesis in many organs as observed in Pearson syndrome. Figure 6-2 shows a simplified view of the pathophysiologic relationship of various mitochondrial diseases in the context of sideroblastic anemias, bone marrow failure, and/or mitochondrial cytopathies.

Sideroblastic anemia in children is often secondary to defects in the enzymes of the heme biosynthetic pathway, namely, ALA-S deficiency. Impaired production of heme resulting from defects in these enzymes results in mitochondrial iron accumulation, damage to the mitochondrial machinery, and formation of ring sideroblasts. Porphyrias, however, do not display sideroblastic anemia because they are characterized by defects in the cytoplasmic steps of heme synthesis.

Toxins or drugs responsible for causing sideroblastic anemia should be eliminated. Oral pyridoxine is used in some patients with either congenital or acquired siderob-lastic anemia with partial response.

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