Introns, protein syntheses and aging

Abstract

In the fungus Podospora, a correlation has recently been established between the presence of circular DNA molecules arising from the mitochondrial genome (SEN-DNAs) and the senescence syndrome. Here, I propose a hypothesis which accounts for the initial event which leads to the first SEN-DNA. A molecule in the most frequent situation where the SEN-DNA is an intron which might code for a maturase. This hypothesis is based upon several observations made either in Podospora or in the yeast S. cerevisiae. It assumes that mitochondrially synthesized maturases are unspecific nucleases able to work at the level of RNA and DNA molecules. Their specificity for RNA splicing instead of DNA is given by cytoplasmic proteins. Therefore, if the balance between cytoplasmic and mitochondrial protein syntheses is disturbed in favour of the mitochondrial compartment, the maturase would be accumulated and allowed to splice introns from DNA instead of RNA molecules. This hypothesis can account for aging of higher eucaryotic cells by postulating analogous processes in their nuclear compartment.Cell compartment RNA maturase Senescence TranslationAging has been very difficult to study in higher eucaryotes because of the complexity of these organisms. Therefore, this phenomenon has been investigated with the use of simplified cell models [l]. Among such experimental models, the fungus Podospora anserina appears as one of the most convenient for two main reasons. First, this organism is well characterized genetically. Second, the senescence phenomenon (arrest of vegetative growth of the mycelium) has been well characterized in Podospora [2,3] and can be controlled by genetic manipulation as well as by changing the culture conditions. Recently, a strict correlation has been established between the presence of circular DNA molecules arising from the mitochondrial genome (SEN-DNAs) and the senescence syndrome [4-81. In spite of this important discovery, two main questions remain to be answered. First, what is the molecular nature of the primary event which leads to the first SEN-DNA molecule and what are the physiological conditions which favour this primary event? Second, how does the presence of SEN:DNA molecules lead to the death of the fungus? A partial response to the second'question has been proposed [9]. The assumption that the amplification of SEN-DNA could be the prime cause of senescence is supported by several lines of data. The most striking is the rejuvenation caused by ethidium bromide which is associated with the loss of SEN-DNA molecules [8]. Here we propose a working hypothesis which tries to answer the two parts of the first question, at least in the cases where the aging event is associated with the CY-SEN-DNA which is the most frequent and the best known situation [7,10]. Based upon 6 relevant sets of data which will be discussed below, this hypothesis can be summarized as follows. The primary event which leads to the production of the u+-SEN-DNA is that an intron-encoded maturase works erroneously, using DNA instead of ...

Variable DNA splicing sites of a mitochondrial intron: relationship to the senescence process in Podospora

“…Either the intron has the property of excision at the DNA level, or the gene is processed by a DNA-DNA recombination event involving a reverse transcript of the mature messenger. The first hypothesis could imply intervention at the DNA level of an RNA maturase encoded by the intron ca (Picard-Bennoun, 1985). The second, postulated to explain the origin of pseudogenes in mammals (Wilde et al, 1982), implies that Podospora possesses a reverse transcriptase which could also be responsible for the synthesis of SEN-DNAca from the corresponding intronic RNA molecules.…”

A site-specific deletion in mitochondrial DNA of Podospora is under the control of nuclear genes.

“…Therefore, the error rate per se does not influence the senescence process. The way in which the cytosolic translational apparatus is involved is not clear (21,26). However, it has been reported that aging in Drosophila is associated with a sharp decline in the rate of synthesis of the translational elongation factor la (EFla) (27).…”