On December 5th, 2023, Professor Ruhong Zhou from Shanghai Institute for Advanced Study, Zhejiang University, together with Professor Bing Tian and Professor Yuejin Hua from College of Life Sciences, Zhejiang University, Professor Yan Qiao from Institute of Chemistry, Chinese Academy of Sciences, published An inorganic mineral-based protocell with prebiotic radiation fitness (DOI: https://doi.org/10.1038/s41467-023-43272-5) in Nature Communications, presenting a radioresistant protocell model with redox reaction system in response to ionizing radiation, which might enable the protocell fitness to prebiotic radiation on the primitive Earth preceding the emergence of enzyme-based fitness.
The appearance of life on the Earth was a result of a series of geochemical events involving the interaction of prebiotic simple inorganic molecules, followed by the formation of biopolymers, such as peptides and polynucleotides, and the emergence of protocells. Protocell fitness under extreme prebiotic conditions is critical in understanding the origin of life. However, little is known about protocell’s survival and fitness under prebiotic radiations.
The authors proposed a model of a radiationresistant, cohesive droplet primitive cell assembled from inorganic minerals and simple biomolecules (Figure 1). Previous studies found that volcanic activity could polymerize phosphates at high temperatures to generate a simple inorganic polymer, polyphosphate (PolyP), which may predate the appearance of nucleic acids and peptides. This work demonstrated that PolyP could form cohesive droplets with divalent metal ions contained in primitive geologic environments e.g., volcanoes and deep-sea vents via liquid-liquid phase separation, for example polyP-Mn droplets, and it could also form droplets with positively charged simple oligopeptides, as polyP-RER droplets for example.
Figure 1. Diagram illustrating the radioresistant protocell model based on phase separation of polyP with simple molecules
Leveraging biochemical and spectroscopy techniques and computational simulations, the authors found that both polyP-Mn and polyP-RER droplets could recruit proteins, but for nucleic acids, the two droplets show distinct properties: polyP-RER could effectively recruit DNA, while polyP-Mn could not. In gamma radiation, polyP-RER droplets disintegrated, leading to DNA and proteins within destroyed, while polyP-Mn droplets did not disintegrate and proteins within were not severely damaged. In addition, droplets formed by polyP with other metal ions e.g., polyP-Fe, polyP-Ca and polyP-Mg could not protect the proteins inside, indicating that polyP-Mn could act as a radiation-resistant chassis. The radiosensitive polyP-tripeptide droplet sequestered with both proteins and DNA could be encapsulated inside the polyP-Mn droplet, and form into a compartmentalized protocell. The protocell protects the inner nucleoid-like condensate through efficient reactive oxygen species’ scavenging capacity of intracellular nonenzymic antioxidants including Mn-phosphate and Mn-peptide. Researchers further noticed that although DNA and nucleic acid molecules could not be absorbed by polyP-Mn, polyP-RER droplets with recruited DNA could fuse with polyP-Mn cohesive droplets (cytoplasmic-like) to form an independent cytoplasmic-like nucleus, and such assembly resembles a primitive cell with multiphase structure. In radiation, such complex maintained morphological integrity to protect nuclear region, intracellular nucleic acids and proteins from reactive oxygen species (ROS) from radiation, thus keeping biological function (Figure 2). The authors further illustrated that Mn-small molecule antioxidants of Mn2+ and free phosphates as well as short peptides may efficiently scavenge reactive oxygen radicals, protecting nucleus-like cell and biomolecules from radiation. This protocell model with fitness under radiation stress could be a candidate for cell evolution from molecular evolution, and the polyP LLPS-based protocell with redox reaction system might be operative in the earliest cells in response to prebiotic radiation stress before the emergence of enzyme-based fitness on the early Earth. Beside the application in prebiotic research, particularly in understanding the impact of radiation on the protocells, the facile compartmental protocell can also be applied in synthetic biologyas bioreactor, and/or in drug delivery of nucleic acid and proteins.
Figure 2. Protection of nucleoid-like condensate and biomacromolecules by small-molecule Mn antioxidants in the protocell after exposed to γ-ray radiation
The study introduced a protocell model based on coacervates of inorganic polyP with simple cationic molecules, supporting a prebiotic and radioresistant mechanism in which proteins and spatially partitioned polynucleotides can be protected by nonenzymatic Mn-small molecule antioxidant complexes against radiation-induced ROS damage. To access the work please visit https://www.nature.com/articles/s41467-023-43272-5.