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Changes in the characteristics and distribution of ferritin in iron-loaded cell cultures.

ABSTRACT: When Chang liver cells are grown in an iron-rich medium for up to 20 weeks, iron loading up to 50 times the normal cellular iron content may be obtained, although ferritin increases only to about 10 times normal. Ferritin has been isolated from such cells, and the isoferritin pattern found on elution from DEAE-Sephadex A-50 by increasing chloride concentrations has been used as a basis for studying changes in the properties of ferritin under conditions of cellular loading. A consistent shift of peak ferritin-elution position to higher chloride concentrations (lower pI) occurs when cells are loaded with ferric nitrilotriacetate for increasing lengths of time. A change in immunoreactivity also takes place on loading, the ratio of ferritin reacting with heart and spleen ferritin antibodies increasing at any particular value of pI. Cells were pulse-labelled with [59Fe]ferric nitrilotriacetate and [3H]leucine followed by non-radioactive iron in the same form. During the 72 h after the synthesis of new protein and its incorporation of iron, there is a slight acid shift in its isoelectric point. This effect is seen in both normal and loaded cells, with the whole spectrum being shifted towards lower pI in the loaded state. These findings suggest that the shift to more acidic ferritins on iron loading and the associated changes in antigenicity may be unrelated to subunit composition.

SUBMITTER: Hoy TG

PROVIDER: S-EPMC1162579 | biostudies-other | 1981 Jan

REPOSITORIES: biostudies-other

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Project description:Cellular growth, function, and protection require proper iron management, and ferritin plays a crucial role as the major iron sequestration and storage protein. Ferritin is a 24 subunit spherical shell protein composed of both light (FTL) and heavy chain (FTH1) subunits, possessing complimentary iron-handling functions and forming three-fold and four-fold pores. Iron uptake through the three-fold pores is well-defined, but the unloading process somewhat less and generally focuses on lysosomal ferritin degradation although it may have an additional, energetically efficient pore mechanism. Hereditary Ferritinopathy (HF) or neuroferritinopathy is an autosomal dominant neurodegenerative disease caused by mutations in the FTL C-terminal sequence, which in turn cause disorder and unraveling at the four-fold pores allowing iron leakage and enhanced formation of toxic, improperly coordinated iron (ICI). Histopathologically, HF is characterized by iron deposition and formation of ferritin inclusion bodies (IBs) as the cells overexpress ferritin in an attempt to address iron accumulation while lacking the ability to clear ferritin and its aggregates. Overexpression and IB formation tax cells materially and energetically, i.e., their synthesis and disposal systems, and may hinder cellular transport and other spatially dependent functions. ICI causes cellular damage to proteins and lipids through reactive oxygen species (ROS) formation because of high levels of brain oxygen, reductants and metabolism, taxing cellular repair. Iron can cause protein aggregation both indirectly by ROS-induced protein modification and destabilization, and directly as with mutant ferritin through C-terminal bridging. Iron release and ferritin degradation are also linked to cellular misfunction through ferritinophagy, which can release sufficient iron to initiate the unique programmed cell death process ferroptosis causing ROS formation and lipid peroxidation. But IB buildup suggests suppressed ferritinophagy, with elevated iron from four-fold pore leakage together with ROS damage and stress leading to a long-term ferroptotic-like state in HF. Several of these processes have parallels in cell line and mouse models. This review addresses the roles of ferritin structure and function within the above-mentioned framework, as they relate to HF and associated disorders characterized by abnormal iron accumulation, protein aggregation, oxidative damage, and the resulting contributions to cumulative cellular stress and death.

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Changes in the characteristics and distribution of ferritin in iron-loaded cell cultures.

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