Life is made of the intimate interaction of metabolism and genetics, both built around the chemistry of the most common elements of the Universe (hydrogen, oxygen, nitrogen, and carbon). The transmissible interaction of metabolic and genetic cycles results in the hypercycles of organization and de-organization of chemical information, of living and non-living. The origin-of-life quest has long been split into several attitudes exemplified by the aphorisms "genetics-first" or "metabolism-first". Recently, the opposition between these approaches has been solved by more unitary theoretical and experimental frames taking into account energetic, evolutionary, proto-metabolic and environmental aspects. Nevertheless, a unitary and simple chemical frame is still needed that could afford both the precursors of the synthetic pathways eventually leading to RNA and to the key components of the central metabolic cycles, possibly connected with the synthesis of fatty acids. In order to approach the problem of the origin of life it is therefore reasonable to start from the assumption that both metabolism and genetics had a common origin, shared a common chemical frame, and were embedded under physical-chemical conditions favourable for the onset of both. The singleness of such a prebiotically productive chemical process would partake of Darwinian advantages over more complex fragmentary chemical systems. The prebiotic chemistry of formamide affords in a single and simple physical-chemical frame nucleic bases, acyclonucleosides, nucleotides, biogenic carboxylic acids, sugars, amino sugars, amino acids and condensing agents. Thus, we suggest the possibility that formamide could have jointly provided the main components for the onset of both (pre)genetic and (pre)metabolic processes. As a note of caution, we discuss the fact that these observations only indicate possible solutions at the level of organic substrates, not at the systemic chemical level.

Liquid formamide has been irradiated by high-energy proton beams in the presence of powdered meteorites, and the products of the catalyzed resulting syntheses were analyzed by mass spectrometry. Relative to the controls (no radiation, or no formamide, or no catalyst), an extremely rich, variegate, and prebiotically relevant panel of compounds was observed. The meteorites tested were representative of the four major classes: iron, stony iron, chondrites, and achondrites. The products obtained were amino acids, carboxylic acids, nucleobases, sugars, and, most notably, four nucleosides: cytidine, uridine, adenosine, and thymidine. In accordance with theoretical studies, the detection of HCN oligomers suggests the occurrence of mechanisms based on the generation of radical cyanide species (CN·) for the synthesis of nucleobases. Given that many of the compounds obtained are key components of extant organisms, these observations contribute to outline plausible exogenous high-energy-based prebiotic scenarios and their possible boundary conditions, as discussed.origin of life | formamide | prebiotic syntheses | nucleosides | meteorites H ypothesizing formamide (FA) as parent molecule, we explored its potentiality in synthetic processes when exposed to proton irradiation. The purpose of this analysis is to verify a possible prebiotic scenario consisting of FA, considered here as starting one-carbon atom material, of proton beams mimicking solar energetic particles as energy source, and of meteorites as catalysts. The rationale of this approach is that the results could help in outlining exogenous prebiotic models and their boundaries.FA (NH 2 CHO) is becoming one of the most intensively studied precursors for prebiotic syntheses of compounds potentially relevant for the origin of life (1-4). FA is a ubiquitous molecule in the universe. It has been detected in galactic centers (Sgr A and Sgr B), in star-forming regions of dense molecular clouds, in high-mass young stellar objects, in the interstellar medium and in comets and satellites (5)(6)(7)(8)(9)(10)(11)(12)(13)(14).With the appropriate mineral as catalyst, different ensembles of intermediates of genetic and metabolic apparatuses are simultaneously synthesized from FA under thermal conditions (i.e., by heating liquid FA between 333 and 453 K at room pressure). DNA and RNA components (15-21), amino acids (22, 23), sugars (24), and carboxylic acids (25, 26) have been obtained. Minerals tune the selectivity of these transformations (1, 2), the mechanistic pathways for the synthesis of nucleobases requiring pyrimidine (27-30) or imidazole intermediates (31,32).Within the solar system, ionizing cosmic radiation is generated by the Sun [solar cosmic rays (SCRs), primarily protons accelerated by flares and coronal mass ejections to energies typically of tens to hundreds megaelectronvolts] and is also formed by particles coming from the deep universe [galactic cosmic rays (GCRs)] (33). The SCRs and GCRs differ in their components and energy spectra, but their overwhelming co...

The problem of the abiotic origin of RNA from prebiotically plausible compounds remains unsolved. As a potential partial solution, we report the spontaneous polymerization of 3',5'-cyclic GMP in water, in formamide, in dimethylformamide, and (in water) in the presence of a Brønsted base such as 1,8-diazabicycloundec-7-ene. The reaction is untemplated, does not require enzymatic activities, is thermodynamically favoured and selectively yields 3',5'-bonded ribopolymers containing as many as 25 nucleotides. We propose a reaction pathway on the basis of 1) the measured stacking of the 3',5'-cyclic monomers, 2) the activation by Brønsted bases, 3) the determination (by MALDI-TOF mass spectrometry, by (31)P NMR, and by specific ribonucleases) of the molecular species produced. The reaction pathway has several of the attributes of a click-like reaction.

In addition to their well-known critical role in energy metabolism, mitochondria are now recognized as the location where various catabolic and anabolic processes, calcium fluxes, various oxygen-nitrogen reactive species, and other signal transduction pathways interact to maintain cell homeostasis and to mediate cellular responses to different stimuli. It is important to consider how pharmacological agents affect mitochondrial biochemistry, not only because of toxicological concerns but also because of potential therapeutic applications. Several potential targets could be envisaged at the mitochondrial level that may underlie the toxic effects of some drugs. Recently, antiviral nucleoside analogs have displayed mitochondrial toxicity through the inhibition of DNA polymerase-gamma (pol-gamma). Other drugs that target different components of mitochondrial channels can disrupt ion homeostasis or interfere with the mitochondrial permeability transition pore. Many known inhibitors of the mitochondrial electron transfer chain act by interfering with one or more of the respiratory chain complexes. Nonsteroidal anti-inflammatory drugs (NSAIDs), for example, may behave as oxidative phosphorylation uncouplers. The mitochondrial toxicity of other drugs seems to depend on free radical production, although the mechanisms have not yet been clarified. Meanwhile, drugs targeting mitochondria have been used to treat mitochondrial dysfunctions. Importantly, drugs that target the mitochondria of cancer cells have been developed recently; such drugs can trigger apoptosis or necrosis of the cancer cells. Thus the aim of this review is to highlight the role of mitochondria in pharmacotoxicology, and to describe whenever possible the main molecular mechanisms underlying unwanted and/or therapeutic effects.

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