This article by Gattermann et al. (2004) [Gattermann et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15571245)] discusses the way mutations in mitochondrial DNA can sometimes cause megaloblastic anemia and hypercellular bone marrow that is characteristic of myelodysplastic syndromes. The authors go on to suggest that some myelodysplastic disorders that produce megaloblastic bone marrow may, in fact, be caused by mtDNA mutations. The authors note that mitochondrial iron deposition would be expected to increase the production of reactive oxygen species and damage mtDNA, and authors state that the megaloblastic bone marrow in myelodysplastic conditions, a characteristic of the bone marrow and the circulating, immature red blood cells (RBC) that may result from mtDNA mutations in RBC precursors, is not produced by folate or cobalamin depletion. The implication is that folate and cobalamin produce megaloblastic anemia by mechanisms that are independent of mtDNA damage in reticulocytes or less differentiated, CD34+ cells in the bone marrow. But is this the case?
Cerebral folate deficiency has been associated with the presence of neurological symptoms and mtDNA deletions of indeterminate causes that are ameliorated by reduced folates [Pineda et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16365882) (http://www.bh4.org/pdf/pineda.pdf)], and dietary folate depletion produced, in the livers of rats within four weeks, large deletions in mtDNA and reductions in the expression of subunits of respiratory chain enzymes [Chang et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17381984)]. Chou et al. (2007) [Chou et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17709439)] found similar effects and found that the deletions in mtDNA and reductions in mtDNA transcription were accompanied by mitochondrial proliferation, a change that is usually associated with pathology and does not usually produce a full restoration of respiratory-chain function and ATP levels [Sebastiani et al., 2007: (http://content.onlinejacc.org/cgi/content/full/50/14/1362) (http://www.ncbi.nlm.nih.gov/pubmed/17903636)]. In humans, Lim et al. (2001) [Lim et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11583719)] found that serum total homocysteine concentrations varied inversely with the mtDNA contents of lymphocytes in the blood, and serum folate correlated positively with the mtDNA content.
Mutations in mtDNA in erythrocyte precursor cells are known to be associated with sideroblastic anemia, such as in vitamin B6 deficiency or in hereditary, X-linked sideroblastic anemia, but the associations of elevations in the red blood cell ferritin content with folate and cobalamin deficiencies [van der Weyden and Fong, 1984: (http://www.ncbi.nlm.nih.gov/pubmed/6505636)] suggest that a broader range of mechanisms may underlie chronic, cofactor-responsive anemias and cytopenias. Van der Weyden and Fong (1984) found extreme elevations in red blood cell ferritin (RBCF) in people with folate or cobalamin depletion, such that the mean levels of RBCF were between 54 and 74 times the mean value among control patients. The highest RBCF among the people with cobalamin deficiency was 244 times the mean for the control group (van der Weyden and Fong, 1984). Hussein et al. (1978) [Hussein et al., 1978: (http://www.ncbi.nlm.nih.gov/pubmed/644254)] found elevated serum ferritin concentrations in people who had anemia due to cobalamin deficiency. In these people, cobalamin repletion lowered the serum ferritin concentrations within 24-48 hours (Hussein et al., 1978). Cazzola et al. (1983) discussed the association of an elevated RBCF content with reduced rates of hemoglobin biosynthesis in immature RBC [Cazzola et al., 1983: (http://www.ncbi.nlm.nih.gov/pubmed/6626742) (http://bloodjournal.hematologylibrary.org/cgi/reprint/62/5/1078.pdf)], and presumably the drastic elevations in RBCF that can occur in folate or cobalamin deficiencies could increase the production of reactive oxygen species and conceivably damage mtDNA. Although RBCF appears to mainly be present in cytoplasmic granules and to evidently not be deposited in mitochondria, the deleterious effect of an elevated RBCF on erythropoiesis implies that some mitochondrial impairment might exist in that context and not just in strictly-defined, sideroblastic anemia. Normal activities of the respiratory-chain enzymes in the mitochondria of reticulocytes are required for heme biosynthesis, even though most of the steps in heme biosynthesis occur in the cytosol [Gattermann et al., 1997: (http://bloodjournal.hematologylibrary.org/cgi/content/long/90/12/4961) (http://www.ncbi.nlm.nih.gov/pubmed/9389715?dopt=Abstract)] Folate and cobalamin depletion may, for example, cause damage to mtDNA that is not so severe as to produce cells with the classical, ringed-sideroblastic appearance.
The hematological effects of cobalamin and folate depletion are highly variable and can, in fact, take on characteristics of myelodysplastic syndromes. Aslinia et al. (2006) [Aslinia et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16988104) (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1570488)] noted that folate and cobalamin depletion usually cause hypercellular bone marrow and premature, intramedullary (i.e. in the red bone marrow, the medulla) hemolysis of immature red blood cells. Although cobalamin and folate depletion may commonly produce hypercellular marrow, Barshop et al. (1990) [Barshop et al., 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2309761)] noted that people with intracellular cobalamin depletion due to transcobalamin II deficiency may display hypocellular bone marrow and may, given the presence of abnormal lymphocyte precursor cells in conjunction with the hypocellular marrow, be suspected of having or diagnosed with forms of leukemia. Wu et al. (2005) [Wu et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/16251179)] also found hypocellular marrow and pancytopenia in a person with cobalamin C disease, a genetic disorder that impairs the intracellular reduction of cob(III)alamin to cob(II)alamin (i.e. from the Co3+ oxidation state to the Co2+ state). Hemophagocytic lymphohistiocytosis, the condition that the person had manifested in association with the hypocellular marrow and depletion of functional, intracellular cobalamin-derived coenzymes (Wu et al., 2005), has a strong autoimmune component and has been shown to precede or be associated with the development of acute myeloid leukemia [Kumar et al., 2000: (http://www.ncbi.nlm.nih.gov/pubmed/11104028)]. Although the clinical manifestations of those genetic disorders tend to be more severe than the manifestations of cobalamin deficiency, there is no fundamental difference, particularly in transcobalamin II deficiency, in the underlying mechanisms that would lead to the changes in the bone marrow (producing increases or decreases in the numbers of colony-forming units, etc.). One could argue that transcobalamin II may interact with other proteins, following its uptake into endosomes, but the responsiveness of people with transcobalamin II deficiency to high doses of oral or parenteral cobalamins would argue against that hypothesis.
In a similar vein, even some of the consequences of anemia that result from cobalamin deficiency may be difficult to explain, from a mechanistic standpoint. For example, intramedullary hemolysis can elevate the serum bilirubin concentration, produced by the metabolism of heme by heme oxygenase, and also elevate the serum lactate dehydrogenase (LDH) concentration (Aslinia et al., 2006). The LDH enzymes are released from lysed RBC but can also be released from the liver or skeletal muscles in some thrombogenic conditions that produce accelerated rates of hemolysis [Cohen et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9590492)], and the release of liver- or muscle-specific LDH isoforms is thought to result from the ischemia- and thrombosis-induced impairments in the oxygenation of the liver or skeletal muscles (Cohen et al., 1998). Similarly, the jaundice, defined as elevations in serum bilirubin that exceed some level, that can occur in cobalamin deficiency [Joshi et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18822634)] may, as implied by Joshi et al. (2008), be partially the result of a "primary" impairment in hepatic function due to cobalamin depletion. This might result from, for example, the decrease in methylmalonyl-CoA mutase activity that occurs in the liver in response to cobalamin depletion, an effect that reduces the transcription of mitochondrial DNA and the activities of respiratory chain enzymes [Leeds and Brass, 1994: (http://www.jbc.org/cgi/content/abstract/269/6/3947) (http://www.ncbi.nlm.nih.gov/pubmed/7508436?dopt=Abstract)].
It seems to me that folate and cobalamin depletion could produce mtDNA damage in CD34+ cells in the bone marrow, perhaps as a result of the excessive accumulation of RBCF. Lumeng and Li (1974) [Lumeng and Li, 1974: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abstract&artid=333049)] discussed, in the context of acetaldehyde-induced increases in the degradation of pyridoxal-5'-phosphate and pyridoxamine phosphate by a phosphatase enzyme, the general view that pyridoxine deficiency per se, in the absence of some factor disturbing vitamin B6 (pyridoxine) metabolism, has not generally been shown to produce overt, sideroblastic anemia. But the fact that the derangement of vitamin B6 metabolism, by alcohol or another drug, can produce sideroblastic anemia is relevant to an understanding of the mechanisms leading to iron deposition in red blood cell precursor cells. The activity of serine hydroxymethyltransferase is sensitive to pyridoxine status and is reduced in response to pyridoxine depletion [Martinez et al., 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10801907)], and this is one site at which the hematological effects of folate and cobalamin could be expected to overlap with the cellular effects of pyridoxine. Although all or most pyridoxine-responsive anemias are known to result from mutations in delta-aminolevulinic acid synthetase (ALAS) (the rate-limiting enzyme for heme biosynthesis in reticulocytes) that reduce its activity (Gattermann et al., 1997), cobalamin depletion could also reduce ALAS activity by reducing succinyl-CoA availability (succinyl-CoA and glycine are the substrates of ALAS) in reticulocytes. Additionally, heme biosynthesis is coupled to the cell cycle, to DNA replication, in erythroblasts [Paul and Hunter, 1968: (http://www.ncbi.nlm.nih.gov/pubmed/4234214)], and thymidine biosynthesis is dependent on the adequacy of both the overall, intracellular pool of folate-derived cofactors and the availability of pyridoxal-5'-phosphate, derived from pyridoxine, as a cofactor for cytosolic serine hydroxymethyltransferase. Thus, folates, cobalamin, and pyridoxine might influence the pool of thymidine that is available for both nuclear and mitochondrial DNA replication, and limitations in thymidine availability may prevent the reticulocyte maturation-associated decline in the RBCF content. This may lead to mtDNA damage and further impairments in heme biosynthesis, etc. There may be some way of analyzing cells for some intermediate set of characteristics, somewhere between the characteristics of the classical sideroblasts or megaloblastic cells. Large numbers of people over age 65 have "unexplained anemia" [Guralnik et al., 2004: (http://bloodjournal.hematologylibrary.org/cgi/content/long/104/8/2263) (http://www.ncbi.nlm.nih.gov/pubmed/15238427?dopt=Abstract)] and anemia would be expected to be accompanied by reductions in the numbers of bone-marrow-derived, CD34+, endothelial cell progenitor cells. These cells could help to limit the progression of atherosclerotic or ischemic disease, etc.
No comments:
Post a Comment