Calcium in the Early Evolution of Living Systems: a Biohistorical Approach

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1738 Current Organic Chemistry, 2013, 17, 1738-1750 Calcium in the Early Evolution of Living Systems: A Biohistorical Approach

Józef Kazmierczak1, Stephan Kempe2 and Barbara Kremer1*

1Institute of Paleobiology, Polish Academy of Sciences, Twarda 51/55, 00-818 Warsaw, Poland; 2Institut für Angewandte Geowissen- schaften, Technische Universität Darmstadt, Schnittspahnstraße 9, 64287 Darmstadt, Germany

Abstract: The possible role of Ca2+ as a promoter of the major steps in the evolution of early life is reviewed. The existing biological knowledge about the role of calcium in living systems is summarized and compared with the major bio-evolutionary events that occurred during the first three billion years of Earth’s history. It is proposed that secular changes in Ca2+ concentration in the marine realm during the Precambrian were the crucial driving force behind major innovations in the evolution of early life, such as photosynthesis, eukaryogenesis, multicellularity, origin of metazoans, biocalcification and skeletogenesis.

Keywords: Photosynthesis, Eukaryogenesis, multicellularity, Origin of metazoans, Biocalcification, Skeletogenesis, Evolution of early life, Calcium, Alkalinity, Early alkaline ocean.

INTRODUCTION Calcium is a divalent cation (Ca2+), ubiquitous in natural wa- The history of life on Earth appears to begin not long after the ters. It has a variable degree of hydration of 6 to 8 water molecules formation of the planet itself, which started about 4.5 billion years that can be exchanged very rapidly. This makes calcium the fastest ago. From the very beginning, life has been in a constant dynamic binding agent of all the available divalent ions in the environment. 2+ 3 chemical interaction with the environment on which its survival and Mg reacts 10 times slower [2]. Calcium in the sea is derived from diversification depends. What we know about the ecological basis two principal sources: (i) riverine run-off, and (ii) hydrothermal of the early Earth is severely limited, but there is little doubt that solutions emanating from the oceanic crust. niches for life’s emergence were abundantly available [1]. At the Calcium and oxygen are two of the major elements in the time of life’s appearance, conditions on the young Earth were sig- Earth’s crust [3-5]. Both are essential for maintaining the Earth’s nificantly different from those prevailing today. Over a geological ecosystem. A link between calcium and oxygen in living systems is timescale, the biological evolution of life tracked the geological found in the biological molecules which bind Ca2+, where oxygen is evolution of the planet through profound changes in metabolism 2+ usually the atom coordinating the Ca [3,4,6,7]. Yet both O2 and and reproduction, punctuated by extremes, to the limits of adapta- Ca2+ can be toxic, and even lethal, to cells and whole organisms. In tion and even to extinction. The effect of this long evolutionary spite of the abundance of calcium and oxygen in the substances history is manifest in the variety of life forms we have today and which make up the Earth’s crust, it is likely that when life began evolutionary stages that have been preserved in rocks as fossils. 2+ more than 3.5 billion years ago the concentration of free Ca and The cell membrane is the basic boundary between any organism O2 surrounding the first cells was much lower than it is today. and its surroundings. It acts as a dynamic molecular sieve that per- Throughout evolution the physiology of cells has been intimately mits the flow of matter and information from the environment into linked to their pathology, because of the need to develop defense the cell and vice versa. The protein cover alters its conformation mechanisms against chemical attack from Ca2+ or oxygen radicals, through coordination changes or the exchange of metal ions posi- as well as other damaging chemical, physical and biological agents. tioned at the surface of membranes (Fig. 1). Transport of ions and energy transduction is the final outcome. Physical and chemical It has been known for nearly a century that a rise in cytosolic 2+ changes in the environment can be beneficial or detrimental to the free Ca is responsible for initiating cellular events such as move- biota. For instance, upwelling of mineral nutrients will principally ment, secretion, transformation and division [3,6,8-10] (Fig. 2A). 2+ foster primary productivity in the sea. However, an oversupply of Yet a prolonged high level of intracellular free Ca irreversibly certain elements, even essential ones, may subject an organism to damages mitochondria and can cause chromatin condensation, pre- stress. Accordingly, cellular systems have to develop counteractive cipitation of phosphate and protein and activation of degradative measures to overcome the threat imposed by their habitat. In order enzymes such as proteases, nucleases and phospholipases [11] (Fig. to illustrate the kind of defense strategies adopted by life over the 2B). course of time for managing hazardous compounds, the case of It has been proven that very high concentrations of Ca2+ can 2+ Ca is presented. This element is an especially sensitive indicator lead to the disintegration of cells and that this process is controlled because the cell has to maintain a critical level of it at all times and through the activity of Ca2+-sensitive protein-digesting enzymes any changes, up or down, will severely impair the cell and eventu- [12]. Calcium is also involved in the programmed cell death known ally kill it. 2+ as apoptosis. The Ca signaling mechanism, which triggers a new

life at fertilization and is then re-used to regulate the developmental *Address correspondence to this author at the Institute of Paleobiology, Polish Acad- program, is suddenly transformed from a signal of life to a signal of emy of Sciences, Twarda 51/55, 00-818 Warsaw, Poland; Tel: +4822 69 78 886; death [12]. Fax: +4822 620 62 25; E-mail: [email protected]

Fig. (1). Mechanisms involved in the detoxification and transformation of metals in living cells. Biomineral formation (black rectangles and dots) may be biologically induced (i.e. caused by physico-chemical environmental changes mediated by the cells), or biologically (i.e. enzymatically) controlled (from [240]).

environmental conditions is for all cells a crucial condition for survival. The complex role of calcium in a living system and its strictly controlled concentration in cytosol must be an early imprinted signal carried by the cell, probably since the beginning of the first living systems. What happened in the early Earth environment to cause this ion to play such a universal role in living systems? What is the role of the calcium ion in the origin of life and major steps in its evolution? When was this role of calcium in living systems established? When and how did signaling pathways and networks originally emerge? What was the Ca2+ concentration in the Earth’s earliest seas and what can Ca2+ tell us about the environment of the early Earth? The purpose of this review is to show the role of Ca2+ as a promoter in the major steps of the evolution of early life. We summa- rize the existing knowledge on the tremendous role of calcium in living systems and we attempt to confront and compare it with the major geological and bio-evolutionary events that occurred on Earth during its first three billion years. We propose that secular changes in the marine Ca2+ concentration of the Precambrian were the crucial force driving major innovations in life, such as multicellularity, photosynthesis, origin of eukaryotes, origin of metazoans, biomineralization and skeletogenesis.

CALCIUM IN THE SEA Today’s Sinks and Sources of Ca2+ The salinity of the modern ocean is rather uniform due to the rapid, approximately 103 years, thermohaline mixing by what is Fig. (2). A: Examples of phenomena activated by an increase in intracellular known as the “global conveyor belt” [13]). Common salt, NaCl, is free Ca2+ (after [3], modified). B: Mechanisms involved in Ca2+-mediated its main solute. There is only a small reservoir of dissolved carbon- cell killing (after [11], simplified). ates; this, however, is of special interest in our context, since Ca2+ 2+ - Is it only a coincidence that the simple calcium ion acts during and Mg are the principal counterions of HCO3 . Globally, surface cell birth, life and death, and that it regulates so many different sea water is substantially supersaturated with respect to calcite and cellular processes? The ability to sense and respond appropriately to aragonite, the two main polymorphs of CaCO3, and is highly super-

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Fig. (3). A: Model of ocean development through Earth’s history (after [25]). B: A dissolution experiment with a sample of pulverized primordial crust (2.7- billion-year-old komatiite of the Abitibi Greenstone Belt, Canada) was carried out to support the primary highly alkaline character of the early ocean postulated by the model. The rock powder was stirred continuously for several weeks in 500 ml of distilled water at a temperature of 18–22°C, and a lab pCO2 ~600ppmv. A solution rich in Mg2+, with Ca2+ and Na+ in lower concentrations and K+ and Fe3+ occurring in only minor amounts, resulted. Ca- and Mg- carbonates would precipitate, leaving Na- and K-carbonates behind and making the solution progressively more alkaline (from [116]). saturated with regard to dolomite. This disequilibrium state is at- Chemical Evolution of an Early Ca2+-Poor Ocean tributed to the presence of a series of inhibitors, most notably mag- Cytosolic Ca2+content in all non-excitable (resting) cells is kept nesium and dissolved organic matter, that interfere with the nuclea- constant at ~10-7.5 M and is thus lower by several orders of magni- tion of a CaCO3 crystal seed. It has been suggested that inorganic tude than in extracellular fluids such as blood or seawater (10-2 to 5 precipitation of CaCO3 in average sea water would require 10 years 10-4 M). Concentrations above the critical 10-7 M are considered 2- [14]. With increased water depth the carbonate ion (CO3 ) count deleterious to cell function [18], showing that the seawater of today, decreases and the solubility of first aragonite and then calcite is containing 20 meq Ca/l, must be considered lethally toxic to cytosol surpassed, causing them to be dissolved in the lower part of the functioning. It has been proposed that life originated in an environ- ocean, i.e., below the “carbonate compensation depth” (CCD) [15]. ment with Ca2+ concentrations at cytosolic level [19], evolved by 2+ Due to supersaturation, extraction of CaCO3 from the upper adjusting to increasing higher Ca levels and developed elaborate ocean is almost entirely biologically mediated, except in a very few devices to maintain its continuation [20]. This implies that the restricted shallow seas, where CaCO3 can chemically precipitate. chemistry of a prebiotic sea – as far as calcium is concerned – was 2+ Expressed differently, removal of Ca from the sea is not a ques- entirely different from that of modern oceans. Moreover, the growth tion of carbonate mineral equilibria. Instead, biomineralization of Ca2+ by four orders of magnitude over 4 Ga must have imposed a (which is enzymatically regulated and thus an irreversible thermo- formidable stress upon the evolving biota. 2+ dynamic process) controls Ca in the sea [16]. This situation is A wide range of opinions exists as to the chemical nature and identical to that of molecular oxygen in air, whose level is princi- chemical evolution of the early sea [21-24]. Most authors maintain pally biologically determined. that the early ocean was acidic for a long time, arguing that the 2+ Ca in the modern ocean becomes recharged via hydrothermal degassing of Earth would produce the CO2-rich atmosphere needed channels, pore waters and terrestrial run-off at a ratio of 25:10:65 to keep the oceans from freezing and to counterbalance the lower [17]. Major sinks are calcareous remains of phyto- and zooplankters luminosity of the early sun (“faint early sun”). However, we present accumulating on the sea floor and the remains of benthic biota in a scenario which conforms with geological observations as well as more shallow sections of the ocean. with biochemical requirements [25-29] (Fig. 3A). Accepting the

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Fig. (4). Examples of modern alkaline lakes whose hydrochemistry and mineralizing microbial mats represent analogs of the early alkaline (sodic) ocean and its microbially mediated biosedimentary structures. A-C: Lake Van, Turkey – the world’s largest soda lake with fine particles of calcium carbonate (whitings) precipitating in the water column in areas of inflowing rivers and streams (A), and cyanobacterial microbialites (B, C) accreting on the bottom at ground water inlets. D-F: Lake Alchichica, Mexico – an alkaline crater lake generating along the shore, to the depth of ca. 20 m, huge masses of carbonate cyanobacterial microbialites (D, E) with textures (F) similar to those known from some Precambrian calcareous stromatolites. G: Silicified carbonate stratiform stromatolites from the low energy tidal flat environment of a Paleoarchean (~3000-Myr-old) sea; White Umfolozi section, Pongola Supergroup, South Africa. Scales bars: B - 10 cm; C - 5 cm; E - 1 m; F - 0.1 mm. viewpoint that outgassing of crust and mantle generated sea and air, If one wishes to study conditions similar to the beginning of the chemistry of the ancient ocean should be determined by the early Earth, one has to look for settings rich in fresh volcanic “Urey Reaction” [30], i.e. silicate weathering under the influence of glasses, water and CO2, such as current crater lakes. As a rule these carbonic acid. The mixture of water, CO2 and fresh silicate glasses, quickly become alkaline after an initial acidic phase. The examples made available by the high volcanic activity on the early Earth and we have studied include the crater lakes of Satonda (Sumbawa, especially during the terminal cataclysm (ca. 3.8 Ga ago) when Indonesia) [34-38] and Kauhako (Molokai, Hawaii) [39], both filled impacts spread komatiitic glasses around the globe, is not stable on with seawater; Niuafo‘ou (Tonga) [29,40,41], filled with derived geological time scales (Fig. 3B). Consumption of atmospheric CO2 rain water; and Alchichica (Puebla, Mexico) [42] filled with ground by continental weathering even today amounts to 0.185 Gt C/a [31]. water (Fig. 4D-F). All have become alkaline, with alkalinities of With this rate of CO2 consumption a volume of CO2 comparable to 4.2 (pH 8.6; Oct. 1996), 3.74 (pH 8.22; March 2000), 15.7 (pH today’s atmospheric pool would be consumed within 5000 a. That 8.34; June 1998) and 31.1 (pH 8.89; June 2007) meq/l at the sur- the atmosphere is not quickly depleted is due to back-fluxes from face, respectively – values much higher than current seawater (2.32 the lithosphere such as present-day volcanic activity that is esti- meq/l at the surface; see [15]). We also investigated the largest soda mated to range from 0.05 to 0.12 Gt C/a [32], oxidation of sedimen- lake currently existing, Lake Van (Eastern Anatolia, Turkey) tary organics, CO2 degassing from the ocean due to CaCO3 precipi- [43,44] with an alkalinity of 151 meq/l and a pH of 9.73 at the sur- tation, etc. All these fluxes are small compared to the annual ex- face (Fig. 4A-C). As to the genesis of this excess alkalinity (com- change of CO2 between the ocean and the biosphere on one side pared to average seawater), the Urey reaction is responsible for the and the atmosphere on the other (ca. 70 and 120 Gt C/a, respec- crater lakes of Niuafo‘ou and Alchichica, here formulated for the tively); compare IPCC [33]. With the terrestrial biosphere missing weathering of an average continental crust plagioclase: in pre-Silurian times, the largest of these fluxes did not exist; the Na0.62Ca0.38Al1.38Si2.62O8 + H2CO3 kaolinite + SiO2 + 0.6 + 2+ - 2- + carbon cycle was therefore much slower than today and less Na + 0.4 Ca + 0.6 HCO3 + 0.4 CO3 + H (1) temperature- and moisture-dependent.

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2+ 3- Lake Van most probably acquires its alkalinity in a similar way, result also from the very low solubility product of [Ca ] and [PO4 ], but its waters derive from tributary rivers that have, in part, equiva- leading to fast precipitation of calcium phosphate within the cell, 2+ 2+ - 2- lent concentration ratios Ca +Mg < HCO3 +CO3 or, phrased which is deleterious to cell functioning. Therefore, universal phos- + + - 2- differently, Na +K > Cl +SO4 , preconditions that lead to alkaline phate-based cell energetics is probably of very ancient origin and is conditions when subject to long-term evaporation in terminal lakes not compatible with high concentrations of Ca2+ in cytosol at a [45]. Satonda and Kahauko, on the other hand, are, because of their neutral or basic pH typical for the cytosol [20,60]. high sulfate concentration derived from seawater, subject to the Three factors are responsible for keeping such a low level of “alkalinity pump” [27]. This produces alkalinity through microbial Ca2+ in the cytosol: (i) low permeability of the cell envelope con- sulfate reduction of organic matter during which the charge of the trolled by influx mechanisms, (ii) a high buffering capacity, and sulfate ion is replaced by bicarbonate ions according to: (iii) an effective export system [61]. In prokaryotic and eukaryotic 2- - C106H263O110N16P1 + 53 SO4 + 14 H2O 53H2S + 106HCO3 cells a number of mechanisms have been developed to control cyto- 2- + - + HPO4 + 16NH4 + 14OH (2) solic Ca concentration. This appears to be an ancient and universal This pathway of alkalinity production in anaerobic water bodies feature of all living creatures [20] and is critically important for cell 2+ is also observed in the present Black Sea, the largest anaerobic functioning [3,10,48,50,59,62]. Ca concentration in cytoplasma 2+ -7 brackish-marine water body existing today [27,46]. ([Ca ]i) is 10 M in all nonactivated cells, which is about four Conditions that match the soda ocean model are reproduced in orders of magnitude lower than the extracellular calcium concentration ([Ca2+]o), ca. 10-3 M in blood and other body fluids, and modern soda lakes found in the vicinity of active volcanoes world- -2 + 2- - ca. 10 M in seawater. wide. Major ions are Na , CO3 and HCO3 . High pH’s (9-11) and 2+ 2+ high alkalinities induce CaCO3-precipitation and keep Ca at a Such an extremely asymmetrical distribution of Ca on two close cytosolic level. sides of the plasma membrane allows the generation of both electri- 2+ 9 3 cal and chemical intracellular signals. The rise of the Ca level to An Archean soda ocean of modern size (1.35 10 km H2O) -6 -5 could readily accommodate all crustal carbon (~65 1021 g C) in 10 –10 M activates a wide spectrum of cell processes, for exam- the form of dissolved carbonates without becoming supersaturated. ple: gene expression, mitosis, contraction, secretion of hormones, Following an initial outgassing phase, during which atmospheric neurotransmitters, and exocrine products (Fig. 5). CO2 levels must have been considerable, silicate weathering re- duced atmospheric CO2 in a matter of a few million years to pCO2 values comparable to modern ones. The combined effects of (i) efficient silicate weathering, (ii) rapid gas exchange across the air- sea boundary, (iii) biological activities, (iv) decreasing CO2 emana- tions with time, and (v) buffering capacity of deep ocean water for CO2 additions from hydrothermal sources kept CO2 levels in air low and within a narrow range of 400 ± 200 ppm at all times [47]. It has been assumed that the early soda ocean gradually evolved into an ocean rich in sodium chloride via ‘titration’ by emanating volatile acids such as HCl, lowering its pH and finally reaching a titration point permitting relatively rapid Ca2+ build-up at the end of the Precambrian [25] (Fig. 3A). If our assumptions are correct, across a time envelope of 3 billion years, the primeval concentra- 2+ Fig. (5). Main pathways and stores controlling cytosolic Ca in a eukaryotic tion of calcium in the ocean increased probably from 1,000 to about cell (after [244], modified). 100,000 times [25]. Although Ca2+ is a signal for life and its increased concentration is necessary for it to act as such, prolonged increases in the concen- CALCIUM IN THE CELL tration of Ca2+ can be lethal for the cell [12,51]. Only a certain Calcium functions as a universal intracellular signal responsible range of concentration values of Ca in cytosol is permitted. Ca2+ for controlling many cellular processes (for review see signaling depends on increased levels of intracellular calcium e.g.,[3,12,48-52]). The selection of ionic Ca during the early stage [Ca2+]c, derived either from sources outside the cell [Ca2+]o, or of biogenesis was in all probability dictated by the ionic composi- from stores within the endoplasmic reticulum [Ca2+]ER. Therefore 2+ tion of the early ocean. Among several available cations, Ca took all forms of life require an effective Ca2+ homeostatic system which control over the freshly formed cells [53]. Calcium was chosen will maintain intracellular Ca2+ at a low concentration, i.e., about 2+ because the Ca ion interacts easily with biological molecules due 10,000 to 20,000 times lower than in the extracellular environment to its specific properties, such as flexible coordination chemistry, [59]. In general, the mechanism of Ca2+ signaling depends on an high affinity for carboxylate oxygen (which is the most frequent increase in the intracellular Ca2+ concentration. The Ca2+ concentra- motif in amino acids), rapid binding kinetics, etc. [53,54]. However, tion is lowest when cells are at rest. It rises when a stimulus arrives, there is one disadvantage to having calcium in the cell. All and this is responsible for the changes in cellular activity [51]. Al- 2+ cells maintain Ca concentration in cytosol at a very low level though this mechanism looks simple, there are many variants of it -7 (about 10 M) because only this level guarantees proper cell func- archived by an extensive Ca2+ signaling “toolkit” [51]. All cells 2+ tion (Fig. 5). Higher intracellular Ca concentration causes, for sustain a controlled level of Ca in cytosol by calcium channels (Fig. instance, aggregation of proteins and nucleic acids. At all phyloge- 5). Even the most primitive prokaryotes have plasmalemmal Ca2+ netic stages, from the most simple bacteria to the most specialized pumps and a Ca2+/H+ and Na+/Ca2+ exchange system [59,63,64]. 2+ eukaryotic cells, Ca exerts a toxic action following uncontrolled Genomic studies are beginning to reveal the widespread occurrence inflow to cells [12,55-59]. The negative cytosolic effects of calcium of conserved channel types likely to be involved in Ca2+ signaling.

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However, due to many ancient gene losses and horizontal gene nitrogen bases and favors their condensation into nucleotides in the transfers, many of the widespread “ancient” channel types appear to presence of phosphorylated ribose [111-114]. have been lost by certain groups [65]. Evolution of Precambrian life can be described in terms of five milestones. These are: biogenesis, origin of prokaryotic and eu- CALCIUM IN BIOHISTORY karyotic organization, multicellularity, origin of metazoans, and Calcium and Biogenesis skeletogenesis (biomineralization). Here several puzzling questions immediately arise: (i) Why did life exist only on a prokaryotic level Despite many years of investigation, there is no commonly ac- for ca. 1.5 Ga after biogenesis? (ii) What were the causes of eu- cepted theory on the origin of life (for extensive reviews see, e.g., karyogenesis? (iii) Why, after the appearance of eukaryotes, did [66-77]). The causes and modes of the early evolution of prokary- only microorganisms exist for almost 2 Ga? (iv) What were the otic and eukaryotic organisms remain an enigma as well [78-82]. causes of metazoan origin? (v) What caused the explosion of min- Not only the time frame of biogenesis is problematic, but also the eral skeletons close to the Precambrian/Cambrian boundary? geochemical conditions forming the environmental setting during Calcium is one of the most ubiquitous metal ions in cellular that time (e.g. [25,27,83-87]). Unfortunately, the very limited re- systems [2] controlling almost all life processes [12,52], such as cord of Eoarchean to Paleoarchean (ca. 3.85-3.2 Ga) rocks hinders triggering life at fertilization and the development and differentia- our search for a detailed record of earliest life forms. Any attempt at tion of cells into specialized types [12]. It also controls the activity reconstructions of environmental conditions for the earliest times is of numerous enzymes, other signaling molecules, transcription unfortunately faced with the daunting task of sifting through a factors, and cytoskeletal components. In other words, cells need thermally and chemically altered and mechanically deformed geo- Ca2+ to correctly and precisely regulate most cell activities. Finally, logical record of the time of evolution’s earliest steps. Nevertheless, calcium is also one of the most versatile and universal signaling some progress has been made in the last decades and it is generally agents also in the human body and acts as an intracellular messen- accepted that life was established considerably more than 3.5 bil- ger, relaying information within cells to regulate their activity. lion years ago (3.8 billion years ago, e.g., [88, 89]). Carbonaceous Therefore, it has been suggested [27,28,115] that continuous change 2+ matter of supposed biological origin has been documented with in marine Ca concentration, associated with changes in TCO2, pH carbon isotope ratios in the range of about -35 to -20‰ for the old- and alkalinity, was presumably a major driving force for biological est rocks of sedimentary origin ([90-93]; for another opinion see evolution throughout Earth’s and possibly other planets' [116] his- [94]). This suggests that by 3.5 Ga at the latest a biogeochemical tory. carbon cycle had been established. It is also possible that this in- cluded both photosynthetic and chemosynthetic means of carbon CALCIUM AND EARLIEST LIFE fixation, but the carbon isotope values cannot differentiate between the two metabolic pathways [95]. The oldest morphological micro- Calcium and Cyanobacteria-like Microfossils fossils are about 3.5 Ga in age [80,96,97]; searches for fossils older Some of the early Archean microfossils described from stroma- than these have so far been unsuccessful. tolites are most likely related to cyanobacteria. The problem of Lately, much new information has been forthcoming concern- proving the biogenicity of such structures has been thoroughly dis- ing the biological potential of environments that might exist else- cussed [117]. All microfossil-like objects known from Archean and where in the solar system, such as on the Jovian moons Europa and Proterozoic formations are represented by small rod-shaped bodies, Ganymede, the Saturnian satellite Enceladus, and, of course, Mars. unornamented coccoids, or sinuous tubular or uniseriate filaments [78,118-120]. Their morphological simplicity is consistent with It has been shown that the oceans occurring below the icy surface their interpretation as descendants of an early-evolving Archean of Europa and Enceladus could be alkaline [98-100], representing microbial evolutionary continuum. the primary environments of these moons. New observations indicate the presence of frozen alkaline fluids in the Martian soil [101, The oldest cyanobacteria-like fossils have been described from 102] and the existence of very old carbonate rocks on the Martian rocks about 3.5 Ga old, e.g., the Apex Basalt, Pilbara Craton, Aus- surface [103], suggesting that the former Martian hydrosphere was tralia and the Onverwacht Group, Barberton greenstone belt, South of an alkaline nature, as inferred by [104]. Africa [96,121-123]. Stromatolitic structures without microbial 2+ evidence are known from similar ages (Strelley Pool Formation, Recently it has been proposed that alkaline (i.e. Ca -poor) environments may have been much more common on the early Earth Western Australia, 3.45 Ga old – see: [124, 125]). All extant cya- than considered previously [74,105], and that these high pH envi- nobacteria are alkalophilic organisms [126] with extremely low ronments, as earlier authors supposed [106-107], might have pro- requirements for calcium [127] and a high requirement for sodium moted the abiotic formation of life blocks [71,74,108]. Such a con- [128]. These requirements seem to be inherited from the earliest clusion was also reached by Ruiz-Bermejo et al. [109], who studied cyanobacteria, which lived in seawater different from today’s. Cal- the role of pH in prebiotic synthesis. Their experiments show that cium stimulates formation of mucilage sheaths in cyanobacteria aerosols formed under simulated alkaline ocean conditions could [129] and, together with magnesium, is the prime factor controlling provide a good environment for the formation of primeval materials cell-to-substrate adhesion of bacterial aggregates [130-132]. 2+ (tholins) believed to be precursors of the emergence of life. Alka- Fletcher [133] postulated that Ca may play a role in maintaining line conditions for early life have also been supported by other the structural integrity of bacterial film. This would be in agreement authors. Holm et al. [110] and Holm and Neubeck [111] pointed out with the early appearance of bacterial (cyanobacterial) mats in the that high pH may promote abiotic formation of pentoses, particu- history of life [134] – (see Fig. 4G), and could be interpreted as an larly ribose, a basic constituent of RNA (“RNA world hypothesis” – effect of the local influx of calcium-enriched waters (riverine, hy- for review, see: [112, 113]), from simple organic compounds. drothermal, groundwater seepages) into the Ca2+-poor Archean Higher pH also supports the synthesis of amino acids and purine seawater [27,115]) (Fig. 6). Interestingly, Ca2+ seems to be also

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Fig. (6). Main zones of calcium and pH stress in the highly alkaline (sodic) early Precambrian ocean. The contact of the primordial alkalophilic life thriving in the sodic ocean with the Ca-rich waters from seepages and continental runoff and metal-rich acidic hydrothermal injections is considered to be crucial for the evolution of earliest living systems (from [28]). involved in heterocyst differentiation in cyanobacteria, the special- μm3 [150] and corresponds to a cell diameter of 3.5μm (for spheri- ized cells responsible for atmospheric nitrogen fixation [135]. cal cells). It means that even the oldest carbonaceous spheres, 5-28 Calcium plays also a key role in photosynthetic systems. The μm in diameter, found in the 3.4-Ga deposits of South Africa process of photosynthesis is considered ancient, and was likely well [121,151] could well be remnants of eukaryotic unicells. established on Earth more than 3.5 billion years ago [136]. The A crucial step in the evolution of eukaryotes was undoubtedly nature of the earliest photosynthetic lifestyles is poorly understood the development of the cytoskeleton [142]. There are indications [137]. Divalent Ca ions with Mn(II) are involved in the O2-release that both synthesis and disassembly of the main cytoskeletal pro- step in Photosystem II [138, 139] in a chain reaction that originated teins, tubulin and actin, comprising microtubules and microfila- with the forerunners of cyanobacteria early in the history of life ments, are highly Ca2+-dependent [152-154]. Interestingly, changes [140]. in microtubule organization caused by changing external calcium concentrations are very rapid in some organisms and associated Eukaryogenesis with impressive morphogenetic effects [155-158]. According to the most widely accepted theory, eukaryogenesis was achieved by proto-eukaryotic “host” cells through endocytosis Calcium and Early Unicellular Eukaryotes of chloroplasts and mitochondria symbionts [141-143]. It has been Similarly to prokaryotes, most unicellular algae and fungi ex- experimentally shown that endocytosis (both pinocytosis and hibit low calcium requirements [159, 160]. Good examples from the phagocytosis) is calcium-dependent, with a maximum uptake at 10-4 evolutionary point of view are yeasts, known for their extremely M external Ca2+ level [144, 145]. Transposing this Ca2+ threshold to low requirements for calcium [161,162]. Yeasts are characterized the model of calcium build-up in the Ca-poor early Precambrian by an enormous Ca-sequestering and Ca-storing capacity that can ocean (Fig. 7), it can be concluded that sustenance of the first endo- be interpreted as a physiological relict conserved from the remote symbiotic cellular systems was not possible until the extracellular past, when yeast in calcium-poor primordial habitats had to trap Ca2+ level exceeded 10-5 M. Findings of eukaryote-like microfossils Ca2+ needed for cell regulation. Habitats with such labile Ca2+ lev- in sediments 2.1 Ga old [146] indicate that this level could have els probably characterized areas in the early soda ocean where acid been attained quite early. It is not clear when the genetic material calcium-rich hydrothermal water mixed with highly basic and cal- was shifted to the cell’s interior and became enclosed by a mem- cium-poor oceanic water (Fig. 6). brane forming the nucleus, but this process could have been an Low calcium requirements have also been observed in unicellu- adaptive response to protect the genetic apparatus from increasing lar and coenobial green algae [127,163]. While unquestionably 2+ 2+ concentrations of Ca in the environment. Since nucleic Ca is green microalgae have not yet been identified among early Precam- 2+ regulated independently of cytoplasmic Ca by gating mechanisms brian microfossils, the larger ~3.2-Ga-old unicells, classified com- in the nucleic envelope [147], this implies that the shift of the ge- monly as problematic “acritarchs,” may belong here [164]. Small netic material to the cell interior and its membranization might have (10-15 m in diameter) spherical microfossils known from Early been an adaptive response to protect the genetic material against Archean, 3.4-Ga-old deposits [121] and from Proterozoic 2.4-2.3- 2+ deterioration by excessive influx of Ca due to its build-up in the Ga-old strata [165] may belong here as well. In younger (ca. 2.0- environment. Calcium is known to be involved in cell cycle events, Ga-old) deposits, unicellular acritarch-like microfossils are repre- such as initiation of DNA synthesis, mitosis and cell division [148], sented by forms ornamented with short spines (Eomicrohystridium) and maintenance of chromosome configuration [149]. The trans- or with terminally branching outgrowths (Eoastrion bifurcatum) formation to a well-organized inner structure containing genetic [118,166,167]. During the Proterozoic unicellular forms of eukary- material could have happened as early as in the Archean, because otic life increased enormously in diversity [79,168-172]. Near the critical mass limit for a dividing eukaryotic cell is approximately 26 turn of the Precambrian/Cambrian some of the spherical unicells

Calcium in the Early Evolution of Living Systems: A Biohistorical Approach Current Organic Chemistry, 2013, Vol. 17, No. 16 1745 attained impressive millimetric sizes for unicellular microorgan- develop and prosper [59]. This called for more sophisticated and isms, while others evolved in a great variety of shapes [173-177]. It effective pathways of Ca2+ signaling [59]. The necessity for precise has been argued that this long-term trend in unicell (“acritarchs”) control over cytosolic Ca2+ concentration forced cells to create a evolution can be linked to a continuous increase of Ca2+ concentra- Ca2+ handling system (signaling “toolkit”), which developed sev- tion in their habitat associated with the synergistic action of other eral controlling pathways. Such a system must have appeared quite metal ions and high phosphate levels [27,28,115]. Such a claim early in evolution, probably more than 3.5 Ga years ago (for the appears to be supported by experimental data showing that the envi- approximate age of the oldest stromatolites see: [117-124]), and ronmental Ca2+ level has a profound impact on both the size and was maintained in phylogeny. The study of choanoflagellates, or- shape of unicellular organisms. For example, according to early ganisms preceding the origin of animals (Metazoa), showed an observations by Stegmann [178], cells of the green microalga Chlo- advanced functional regulation of the Ca2+ signaling “toolkit” [198], rella growing in Ca2+-depleted water are much smaller than cells which means that this “toolkit” was important for the transition from Ca2+-rich media. Kylin and Das [179] reported that cells of the from the single-celled to the colonial state [199]. 2+ green alga Scenedesmus cultivated in a medium with a Ca con- Experiments on extracellular concentration of Ca2+ and other -4 centration below 10 M became smaller and changed shape from divalent cations showed that Ca2+ plays a crucial role in inducing typically spindle-like to ellipsoidal or spherical. Similarly Trainor cell fusion [200-204]. It has been demonstrated that a certain cal- [180] demonstrated that at a Ca2+ level above 10-3 M spiny and -3 cium concentration triggers agglutination of cells, membrane lysis, spindle-like patterns developed in Scenedesmus, but below 10 M and a cell fusion process, which may result in the formation of mul- spherical and spineless morphs dominated the culture. Particularly ticellular syncytia (containing many nuclei) and polykaryons. The prominent varieties of morphotypes have been obtained in the cul- experiments showed that the cell fusion can easily be enhanced by tured siphonalean green alga Acetabularia by changing extracellu- changing the medium conditions to a higher pH (>10) and a tem- lar calcium levels [156,181]. 2+ perature of 37°C, and by the subsequent addition of Ca [205]. In the light of these observations, and the aforementioned ob- These observations could help to clarify the appearance of the earli- served tendencies in the morphological evolution of “acritarch” est multicellular forms in the early alkaline Precambrian ocean. A algae, it seems that three main strategies have been used by unicells sudden local increase in Ca2+ concentration (e.g., at sites of hydro- to cope with continuous Ca2+ build-up in the environment, that is, to thermal activity or river mouths) (Fig. 6) could promote cell fusion achieve a maximal Ca2+ excretionary (read: Ca2+ detoxification!) and multinuclear organization (polykaryons, e.g., some ciliates). In rate: (i) most simply, by increasing the cell diameter, (ii) by devel- the case of algal cell aggregates, coenocytic organizations could be opment of various secondary structures (spines, hairs, etc.) increas- formed (siphonalean algae). ing the cell excretionary surface, and (iii) by a combination of these two strategies. The giant late Proterozoic Chuaria and related forms The signaling role of calcium is well recognized in mammal re- (for review: [176,182,183] are the best evidence for the first strat- production. Life begins at fertilization when the sperm interacts with the egg, which happens because of Ca2+ oscillation that per- egy, whereas for the second and the third, variously sculpted “acri- 2+ tarchs” can be cited [175,184-186]. sists for several hours. The prolonged period of repetitive Ca pulses triggers the developmental program and the cell division It has been suggested [115,187] that near the end of the Pre- cycle, in which Ca2+ activates cleavage to form two daughter cells. cambrian the Ca2+ stress experienced by the planktonic “acritarch” During development, when the final form of the embryo is being algae was intensified by a high level of phosphate in seawater, evi- established, Ca2+ signals are used to control the differentiation of denced by worldwide phosphorite deposits [188,189]. Since in the specific cell types. Ca2+ is also involved in the development of the presence of higher concentrations of extracellular inorganic PO 3- 4 nervous system [12]. calcium migration into cells is greatly enhanced [190], the synergis- 2+ tic action of both ions can produce sublethal or lethal effects [191, The role Ca plays in simple multicellular organisms is best il- 192] associated with copious release of extracellular organic sub- lustrated by the freshwater volvocacean Gonium pectorale. These algae produce colonies composed of 4, 8 or 16 cells. Experiments stances [193] and increase in cell size [194,195]. Late Precambrian 2+ planktonic algae faced with a simultaneous excess of Ca2+ and have shown that the Ca level needed for optimal growth of a 4- 3- cell colony is about 100 times lower than that required for growth PO probably responded in a similar way. 4 of a 16-cell colony. At a very low level of calcium, Gonium cells Calcium and the Origin of Multicellular Life failed to adhere or to produce colonies [206]. Chan [207] demonstrated how the Ca2+ level controls the growth of colonies of the The emergence of multicellular forms of life from single-celled green algae Coelastrum. A medium with a Ca2+ concentration of ancestors was one of the most profound evolutionary transitions in about 210-4 M was able to support the growth of unicells only. In a the history of life. According to new data this might happened sev- medium with a higher (210-3M) Ca2+ level the number of colonies eral times, independently, in different branches of the eukaryotic in the culture increased. A Ca2+ concentration of 10-2 M or higher tree [196, 197]. When did multicellular organisms, which needed had a toxic (inhibitory) effect on Coelastrum. more complex signaling systems (including cell-to-cell communica- The increase in abundance and variety of coenobial and colo- tion), actually start to emerge? It seems that relatively early in evo- nial algae during the late Proterozoic is especially visible in the lution eukaryotic organisms invented cell polarity and cell contacts. Meso- and Neoproterozoic (~1600 to 630 Ma ago) fossil record At the same time, other primitive eukaryotes began to form colo- [79,168-171,185,208-210]. The intensive process of aggregation nies, that is, aggregations of single-celled organisms. This process, of cells during the last part of the Proterozoic was probably en- which can be considered a first step towards multicellularity and hanced by simultaneous excess of Ca2+ and PO 3- in seawater cell specialization, required the development of more complex and 4 [189]. efficient signaling systems. The transition to multicellular organization caused the phenomenon of programmed cell death (apoptosis In metazoan tissues the integrity of cells is also controlled by 2+ or cellular altruism), because some cells had to die to let other cells extracellular Ca concentration. Embryos and tissues of various

1746 Current Organic Chemistry, 2013, Vol. 17, No. 16 Kazmierczak et al.

Fig. (7). Major biological and geochemical events in the Earth’s history shown in relation to temporal changes in marine Ca2+, atmospheric oxygen concentrations, and marine pH values, as implied by the soda ocean model [25] (after [115], modified). animals fail to adhere when extracellular Ca2+ is below 10-4 M universal function of calcium in cell physiology and Ca regulation [211-215]. The most curious example of the role of extracellular and signaling systems functioning in all eukaryotes [219] which Ca2+ concentration in maintaining the integrity of cell aggregates is most probably evolved for keeping the optimal cytoplasmatic Ca2+ provided by experiments with the sponges Microciona and Hali- concentration at a very low level. At some point during the Protero- clona in which cells dissociate when Ca2+ in the medium falls be- zoic, the Ca2+ level in sea water began to rise and the dissolved low 10-5 M but reaggregate when Ca2+ is raised above that level carbonate chemistry became governed by Ca2+ and Mg2+ equilib- [60,199]. It seems that external Ca2+ concentrations between 10-5 rium. Such a rise could have been triggered, for example, by a rapid and 10-4 M were the prerequisite for the origin of multicellular life increase in dissolved sulfate in the ocean caused in turn by the in- in the marine realm. Such concentrations could have been reached crease of oxygen in the atmosphere, again forming a link between quite early (at least in some areas in the early ocean – see Figs. 3A Ca and O2. It should be noted that the end of Proterozoic (Ediacaran and 7), probably during the transition of the Archean to the Protero- period) was a time of great change in the marine realm associated zoic, as a result of decreased alkalinity and intensified riverine input with post-glacial oceanic geochemical overturns documented with of Ca2+ due to rapid cratonization of the lithosphere at that time carbon, calcium and boron isotope proxies [220-224]. [216, 217]. The advance in Ca-regulation and Ca-extrusion systems Organisms had to respond to that change [221]. The biocalcifi- in eukaryotes was probably the result of these shifts (Fig. 7) and the cation at about the Precambrian/Cambrian boundary was most evolution of a whole spectrum of calcium-binding and calcium- probably driven by the rise in Ca2+ concentration in the shelf seas to modulated proteins used later by metazoan organisms [60,199]. The levels sub-toxic or toxic to biota [27,115,187, 221, 225-233]. This recent finding of 2.1-Ga-old large fossils described as the oldest event and fluctuating Ca2+ levels in the Phanerozoic seas [234] are colonial microorganisms [218] seems to support such a claim. Al- supposed to have challenged a variety of protists and invertebrates though this finding is highly speculative, the possibility of a much to respond (i.e. to detoxify) by depositing calcareous skeletons of earlier appearance of colonial eukaryotic organisms cannot be com- various thicknesses and cyanobacterial mats to calcify in vivo at pletely excluded and should be taken into consideration in future various rates [187, 235, 236]. The biocalcification event at the Pre- studies. cambrian/Cambrian boundary finally changed carbonate deposition from a chemical to predominantly an enzymatic process, in which 2+ Biocalcification and Skeletogenesis extraction of Ca from the Phanerozoic sea became the domain of organisms. It should be noted, however, that many organisms also Finally, the Ca-detoxification hypothesis considers the onset of 2+ biocalcification at the Precambrian/Cambrian transition as a com- responded to Ca and other metal ion stress by secreting complex mon reaction of marine macrobiota to rapid exposure to subtoxic molecules such as polysaccharides or glycoproteins. These mole- 2+ cules interact with calcium and other metals forming organometal- Ca concentration after a longer existence in relatively calcium- poor environments [27,115,187]. This hypothesis is based on the lic complexes of high buffering capacities [193, 235, 237-243].

Calcium in the Early Evolution of Living Systems: A Biohistorical Approach Current Organic Chemistry, 2013, Vol. 17, No. 16 1747

CONCLUDING REMARKS [15] Broecker, W.S; Peng, T.-H. Tracers in the Sea. El Digio Press, Lamont- Doherty Geological Observatory, Palisades, N.Y. 1982. We suggest that the initial low concentration and the consecu- [16] Degens, E.T. Molecular mechanisms on carbonate, phosphate, and silica 2+ deposition in the living cell. Topics Current Chem,. 1976, 64, 1-112. tive build-up of Ca in the Precambrian sea was one of the prime [17] Shiller, A.M.; Gieskes, J.M. Processes affecting the oceanic distribution of agents behind the origin and evolution of life. Although such a dissolved calcium and alkalinity. J. Geophys. Res., 1980, 85, 2719-2727. statement may seem controversial, integrated knowledge from a [18] Kretsinger, R.H.; Nelson D.J. Calcium in biological systems. Coord. Chem. Rev., 1976, 18, 29-124. wide spectrum of geological, chemical and biological sciences sup- [19] MacCallum, A.B. The paleochemistry of the body fluids and tissues. Physiol. ports this scenario. 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Received: April 10, 2011 Revised: May 07, 2013 Accepted: May 12, 2013