Multiple Enzymatic Defects in Mitochondria in Hematological Cells of Patients with Primary Sideroblastic Anemia

Abstract

A B S T R A C T Activities of mitochondrial enzymes in blood cells from 69 patients with primary sideroblastic anemia were determined to elucidate the pathogenesis ofthe disease. In erythroblasts of patients with primary acquired type the activities of both 8-aminolevulinic acid synthetase and mitochondrial serine protease were inevitably decreased. The susceptibility to the protease of apo-8-aminolevulinic acid synthetase prepared from erythroblasts of patients with this type was within the normal range, in contrast to that of pyridoxineresponsive anemia. The activities of mitochondrial enzymes such as cytochrome oxidase, serine protease, and oligomycin-sensitive ATPase, except citrate synthetase, were usually decreased in mature granulocytes of the patients. Patients with hereditary sideroblastic anemia also had decreased 8-aminolevulinic acid synthetase activity in erythroblasts, and decreased serine protease activity in both erythroblasts and mature granulocytes. Mature granulocytes obtained from patients with pyridoxine-responsive anemia before therapy had decreased cytochrome oxidase activity, however, the activity increased to a normal level when the patients were in remission. The activities of other mitochondrial enzymes in mature granulocytes were within normal range in these patients before pyridoxine therapy. The activities of these mitochondrial enzymes in lymphocytes were within normal range in all groups of patients with primary sideroblastic anemia.We suggest that patients with primary acquired, and possibly also those with hereditary sideroblastic anemia have impaired mitochondrial function in both erythroblasts and granulocytes. That only anemia is observed in these patients is because a functional abnomiality of mitochondria in erythroblasts is most important because of the role of mitochondria in the fomiation of heme in erythrocyte development. In con-

A study of a female with congenital sideroblastic anemia

“…ALA synthetase, which catalyzes the step of ALA formation from succinyl Coenzyme A (Co-A) and glycine, is the rate-limiting enzyme in the heme synthetic pathway, and reduction of ALA synthetase activity in erythroblasts is probably the primary defect in most patients with primary SA [3-51. Recently Aoki et a1 [8] demonstrated that mitochondrial enzymes of granulocytes (eg, neutral protease, oligomycin-sensitive ATPase, etc) have low activity in hereditary and primary acquired SA. Accordingly there may be impairment of mitochondria of both erythroblasts and granulocytes in these cases.…”

“…Inactuation of apo-ALA synthetase by the protease was expressed as the unit of susceptibility: 1 SU was defined as the degree of inactivation losing one-half of the activity in 30 min when 100 U of the protease was added to the incubation mixture. Other enzyme assays were measured as described earlier [8].…”

“…Almost all these features have been ascribed to a defective heme synthesis pathway (especially a defect in 6-aminolevulinic acid (ALA) synthesis) in erythroblasts [ I , 21. Recent biochemical studies on bone marrow in SA have demonstrated reduced activity of ALA synthetase except in the secondary cases [3-5).Recent reports have also shown that the activity of mitochondria1 neutral protease, which inactivates the apo form of ALA synthetase [6,7] is decreased in the hereditary and primary acquired cases [8], whereas it is normal in the pyridoxine-responsive cases [8,9]. Moreover, the sensitivity of the apo form of ALA synthetase to the neutral protease was markedly increased in pyridoxine-responsive cases [9], whereas it is normal in the hereditary and primary acquired cases (81.…”

Enhanced growth of myelodysplastic colonies in hypoxic conditions

“…Accumulating evidence for a low oxygen tension in the-hematopoietic stem cell (HSC) niche and a rising gradient of oxygen tension during subsequent differentiation [49][50][51][52][53][54][55][56][57], as well as reports of mitochondrial dysfunction and oxidative damage in MDS marrows [58][59][60][61][62][63][64][65][66], led us to hypothesize that MDS results from a lesion that causes apoptosis only at oxygen tensions higher than that of the HSC niche. Such a lesion would permit unlimited self-renewal of MDS-initiating cells, provided these cells stayed at an oxygen tension comparable to that of the HSC niche.…”

Medullasin enhances human natural killer cell activity.

“…From subcellular fracReceived for publication 2 August 1981 and in revised form 28 January 1982. tionation studies using rat erythroblasts as the material, medullasin is considered to be located on the inner mitochondrial membrane. Medullasin in erythroblasts was shown to participate in the development of a certain kind of anemia (2,3). In the course of investigating the biologic significance of medullasin in granulocytes we found that levels of medullasin in granulocytes were elevated in certain pathological conditions such as chronic inflammations and cancer (submitted for publication).…”