11 - Mitochondrial mutations as modifiers of hemochromatosis

Summary

In health, mitochondria are crucial organelles for iron metabolism and heme synthesis, and contain a specific iron importer known as mitoferrin. In disease, mutations in ALAS2 or ABCB7 result in impaired heme synthesis with the consequent accumulation of iron in mitochondria. In a zebrafish mutant, frascati, there is profound hypochromic anemia and erythroid maturation arrest due to defective mitochondrial iron uptake, although a human counterpart of this zebrafish mutant has not been described to date. Heteroplasmic point mutations of mitochondrial DNA (mtDNA) affecting subunit I of cytochrome c oxidase have been identified in patients with acquired idiopathic sideroblastic anemia. Mitochondria, especially those of hepatocytes, may be injured by iron overload through diverse mechanisms.

Heteroplasmy in certain regions of mtDNA, including that of the non-coding mitochondrial polymorphism at nt 16189, seems to be inherited and is not the result of somatic age-related accumulation. In several populations, the mtDNA 16189 variant is associated with type 2 diabetes mellitus, dilated cardiomyopathy, and low body fat at birth. The 16189 variant lies close to conserved sequences that control replication and transcription of mitochondrial DNA, and it has been proposed that this variant may induce replication slippage. Thus, the 16189 polymorphism has been investigated as a possible heritable factor or “modifier” that could influence the severity of iron overload in HFE hemochromatosis or in other conditions.