Origins and consequences of mitochondrial decline in nucleated erythrocytes

Abstract

Cellular aging in nucleated erythrocytes from lower vertebrates is accompanied by losses in mitochondria but it remains unclear (i) how these losses accrue (ii) if these changes alter energetics and (iii) whether such changes increase the propensity for apoptosis. We addressed these questions using trout erythrocytes that were separated into age classes using inherent differences in buoyant density. The oldest cells showed a profound decline in mtDNA transcripts, due to reductions in both transcription (90% decline in total RNA) and mtDNA copy number (35%). No alterations in the ratio of 16S rRNA to COX I mRNA were detected, nor was there an accumulation of unprocessed mtDNA transcripts. While older cells had reduced basal respiration, there were no changes in mitochondrial enzymes stoichiometries, tissue ATP levels or dinitrophenol-induced (maximal) respiration rates. Apoptosis could not be induced in either whole blood, young or old erythrocytes by pro-oxidants, mitochondrial inhibitors or staurosporine. In contrast, cyclosporin A (CsA) caused caspase 3 activation, DNA laddering and LDH leakage, but only in young cells. Both CsA and a combination of azide, oligomycin and dinitrophenol cause mitochondrial depolarization and caspase 9 activation, but only CsA induced caspase 3 and apoptosis. Caspase inhibitor studies support the conclusion that mitochondrial changes may accompany CsA-induced cell death, but are not essential in its progression. While pifithrin failed to induce cell death, it enhanced the effects of CsA, implicating a role for p53. Collectively, these studies suggest that the mitochondrial changes with aging do not compromise cellular function, although trout erythrocytes can initiate apoptosis by non-mitochondrial pathways.

Muscle remodeling in relation to blood supply: implications for seasonal changes in mitochondrial enzymes

“…However, erythrocyte DNA levels in whole blood (~0.3·mg·g -1 blood; Moyes et al, 2002) are much lower than heart DNA levels (3·mg·g -1 tissue; Leary et al, 1998). Similarly, the levels of mtDNA do not appreciably influence total DNA levels in these tissues.…”

“…While the antioxidant capacities of erythrocytes do not deteriorate with cell age (e.g. Moyes et al, 2002), reduced penetration of the vascular beds could impair erythrocytedependent antioxidant capacities. Thus, seasonal changes in erythrocyte properties could contribute to the remodeling of both the vasculature and energetics in skeletal muscle.…”

The Epimmunity Theory: The Single Cell Defenses against Infectious and Genetic Diseases

“…They are also prone to infections depending on the receptors they express; cellular receptors can be parasitized by a variety of viruses (6). The following hypothetical example illustrates the importance of enucleation of mammalian erythroblasts and the inactivation of nuclei of avian erythrocytes (7) (and other vertebrates) in evading genetic and infectious diseases. Hypothetically, if one particle of a lytic virus were to release 50 particles every hour after invading a single human ME, then all circulating MEs of an individual will be lysed and death will occur in few hours (less than 10 h post infection).…”

“…Avian erythrocytes have active mitochondria (14) that are lost together with ribosomes and cellular RNA in aging nucleated erythrocytes (13, 15). In rainbow trout fish, erythrocytes experience many changes throughout their 4- to 6-month life span including loss of mitochondria, ability to mount heat shock response, and reduction in biosynthetic processes (7). …”

Transcriptomic Analysis of Young and Old Erythrocytes of Fish

“…For example, the shape changes from circular to elliptical during maturation (Tavares-Dias, 2006), the membrane of young erythrocytes is more fluid (Lecklin et al, 2000), and old erythrocytes have fewer organelles such as mitochondria (Moyes et al, 2002) and free ribosomes (Phillips et al, 2000). …”