A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis.

Based on a series of experiments, using cultured postmitotic neonatal rat cardiac myocytes as a model system, we present a novel hypothesis of lipofuscin formation. This hypothesis proposes that lipofuscin is formed within secondary lysosomes due to an interplay of two processes, the production of partially reduced oxygen species by mitochondria and the autophagocytotic degradation within secondary lysosomes. Specifically, it is proposed that H2O2 generated by mitochondria and other organelles permeates into the lumen of secondary lysosomes, which contain iron derived from cellular structures undergoing intralysosomal degradation. The interaction between reactive ferrous iron and H2O2 results, via Fenton-type mechanisms, in the generation of hydroxyl free radicals (OH), inducing lipid peroxidation and eventually leading to intermolecular cross-linking and lipofuscin formation. Additionally, mitochondria undergoing intralysosomal decomposition might continue for a certain period to produce superoxide anion radicals (O2-) and thus also H2O2. This model of lipofuscinogenesis could satisfactorily explain the variations observed in the rates of lipofuscinogenesis among different postmitotic cell types in various species. Such variations might arise from a variety of factors including differences in the efficiency of the 'anti-oxidative shield', rate of H2O2 generation, amount of chain-breaking antioxidants, mode of intralysosomal iron chelation, rate of autophagocytosis as well as degree of efficiency of the intralysosomal hydrolytic enzymes.     

Cloning and characterization of RNF6, a novel RING finger gene mapping to 13q12.

Myeloproliferative disorders frequently show deletions or rearrangements of the long arm of chromosome 13. We report here the cloning of RNF6, a new gene that maps close to the chromosome 13 breakpoint in a case of myelofibrosis with a t(4;13)(q26;q12). RNF6 is predicted to encode a 685-amino-acid protein with a coiled-coil domain and a RING-H2 finger at the amino and carboxy terminis, respectively. In addition, we have identified a novel motif, Lys-X-X-Leu/Ile-X-X-Leu/Ile (KIL motif), that is located shortly upstream of a subset of RING-H2 proteins, including RNF6. Drosophila g1, rat Neurodap1, and mouse Praja1. FISH and physical mapping indicated that RNF6 is located at 13q12.2 close to marker D13S1121, and it is oriented from telomere to centromere. RNF6 is not disrupted by the t(4;13).     

Two new species of Garudinia Moore (Lepidoptera: Arctiidae: Lithosiinae) from India

Two new arctiid species, Garudinia pseudosimulana sp. nov. and G. conjuncta sp. nov. are described and illustrated from India.     

Effect of ambient oxygen concentration on lipofuscin accumulation in cultured rat heart myocytes--a novel in vitro model of lipofuscinogenesis

The objective of this study was to elucidate the factors involved in the accumulation of lipofuscin in post-mitotic cells. The hypothesis that oxidative stress accelerates the rate of lipofuscin accumulation was tested by examining the effects of 5%, 20%, and 40% ambient oxygen concentration on lipofuscin content in cultured rat cardiac myocytes. Lipofuscin was quantified by microspectrofluorometry at 7 and 12 days of in vitro age. Lipofuscin-emitted yellow autofluorescence increased in direct relationship to ambient oxygen concentration with age. Transmission electron microscopic examination of the cells after 3, 8, and 12 days in culture indicated a progressive time and oxygen dependent increase in the frequency and size of lipofuscin organelles. The results are interpreted to suggest that oxidative stress is one of the causal factors in the accumulation of lipofuscin.     

The effects of catalase gene overexpression on life span and resistance to oxidative stress in transgenic Drosophila melanogaster.

Oxygen free radicals and hydroperoxides have been postulated to play a causal role in the aging process, implying that antioxidant enzymes may act as longevity determinants. Catalase (H2O2:H2O2 oxidoreductase; EC1.11.1.6) is the sole enzyme involved in the elimination of H2O2 in Drosophila melanogaster; glutathione peroxidase being absent. A genomic fragment containing the Drosophila catalase gene was used to construct transgenic Drosophila lines by means of P element-mediated transformation. Enhanced levels of catalase (up to 80%) did not prolong the life span of flies, nor did they provide improved protection against oxidative stress induced by hyperoxia or paraquat treatment. However, enhanced resistance to hydrogen peroxide was observed in the overexpressors.