Role of Porphyrin Sequestration in the Biogenesis of Iron-Laden Astrocytic Inclusions in Primary Culture

Abstract

Astrocytes in subcortical regions of the mammalian brain progressively accumulate iron-rich, autofluorecent cytoplasmic inclusions as a function of aging. Cysteamine (CSH) accelerates the appearance of this senescent glial phenotype in situ and in primary rat astroglial cultures. Porphyrins have been implicated as the source of orange-red autofluorescence in these glial inclusions. Yet, CSH has been shown to suppress porphyrin-heme biosynthesis in cultured astroglia. To determine whether porphyrin biosynthesis or sequestration participates in the biogenesis of these glial inclusions, the porphyrin precursor, ³H-δ-aminolevulinic acid (³H-ALA) was administered to CSH-exposed and control rat astroglial cultures followed by light and electron microscopic autoradiography. Control cultures exhibited faint orange-red autofluorescence, intense ³H-ALA labeling, numerous normal mitochondria and few cytoplasmic inclusions. In these cells, ³H-ALA labeling largely occurred over normal mitochondria. The CSH-treated astroglia exhibited diminished ³H-ALA labeling and contained numerous orange-red autofluorescent inclusions. The latter manifested internal compartments delimited by double membranes characteristic of damaged mitochondria. The complement of normal mitochondria in the CSH-exposed cells was markedly reduced. In the CSH-treated cells, ³H-ALA labeling predominated over the large multi-compartmental inclusions. CSH attenuates de novo porphyrin-heme biosynthesis in astroglia but may induce punctate orange-red autofluorescence in the cytoplasm of these cells by promoting large numbers of damaged, porphyrin-containing mitochondria to form tight aggregates within the nascent gliosomes.

A non-canonical role of ELN protects from cellular senescence by limiting iron-dependent regulation of gene expression

“…2A ). Alterations in heme synthesis and degradation have been linked with aging, especially heme degradation, which has been shown to increase with age and after exposure to stress [ 12 , 13 ]. Heme oxygenase 1, HMOX1, was identified as the most upregulated gene at this early time point ( Fig.…”

Brain Iron Deposition in Aging and Disease: Role of HO-1

“…14 C]glycine into porphyrin and heme in astroglial cultures before and during the time when augmented iron concentrations are detectable in distended astrocyte mitochondria by microprobe analysis (Brawer, Reichard et al, 1994;H. M. Schipper, Small, Wang, & Brawer, 2002;Wang, Manganaro, & Schipper, 1995).…”