# Cellular Self-Digestion and Persistence in Bacteria
## 2 Why Does Cellular Self-Digestion Occur? Self-digestion in bacteria is a dynamic process that degrades and removes unnecessary or dysfunctional cellular components within the cytoplasm, allowing cells to perform structured deterioration, while recycling key cellular constituents [67; 68; 69; 70; 71; 72]. Although intracellular degradation continually occurs within bacteria to maintain cellular hemostasis, self-digestion occurs in response to specific stressors, such as starvation and nutrient deprivation [70; 73; 74]. In nature, most microorganisms are not afforded an abundance of resources needed for growth and reproduction processes [74], and many bacterial species encounter a scarcity of nutrients in their respective ecosystems [75; 76]. This lack of nutrients may force cells to enter a quiescent physiological state [77], such as dormancy, to survive in nutrient-limited conditions. However, even in such states, microorganisms may not necessarily be fully dormant during the entire starvation period [74; 78], which in nature, can vary from days to years, depending on the ecosystem [74]. For example, microorganisms in salt mines, deep-ocean habitats, ancient rocks, and caves can face starvation periods that may be as lengthy as thousands of years [74; 75; 76; 77; 78; 79; 80; 81; 82; 83]. Some bacterial species (e.g., _Acetonema_, _Bacillus_, _Clostridium_, _Heliobacterium_) can survive this prolonged starvation by forming endospores. Sporulation, a tightly regulated, genetically programmed cellular process, is distinct compared to the normal bacterial growth where cells divide by binary fission to generate two identical daughter cells. In contrast, an asymmetric division is observed during sporulation, resulting in generation of two cells within the same cell wall: a small forespore and a large mother cell that engulfs the forespore [84; 85; 86]. The fully formed spore is released to the environment when the mother cell is completely degraded [84; 85; 86; 87]. We note that persisters and endospores are two distinct phenotypes. While persister cells are often referred to a small subpopulation of non-growing cells in a cell population that can form stochastically or deterministically, endospores are referred to dormant, nonproductive phenotypes produced by certain bacterial species as a result of extreme stress conditions. Unlike in natural environments, bacteria in the laboratory are provided with ample nutrients to support maximum growth [88]. In such nutrient-rich cultures, the doubling time of some bacteria (e.g., _Clostridium perfringens_) can be as fast as 10 min during exponential growth [89]. Upon exhaustion of nutrients, however, bacteria enter the so-called stationary phase, wherein growth cessation occurs, although the cells still exhibit certain metabolic activities [67; 74; 90]. Once bacteria transit from exponential phase to stationary phase, they develop various strategies (e.g., self-digestion) to survive in their nutrient-depleted environment [67; 90; 91; 92; 93]. Notably, before initiating any sort of survival response, upon entrance to stationary phase, bacteria undergo several morphological changes. In particular, cells in stationary phase become smaller in size, and rod-shaped bacteria become more spherical in shape. This results from changes to the cell membrane and cell wall. For example, in _Escherichia coli_ entering stationary phase, the cell envelope becomes more rigid, and stress-bearing peptidoglycan layers increase from 0.7-0.8% to 1.4-1.9% of the cell's dry weight [94]. Moreover, the cell wall becomes more highly cross-linked, and bacteria experience reduced membrane fluidity [67; 95]. Reductive division, a process by which cells complete their final rounds of cell division in early-stationary phase, without increasing their biomass, also causes them to become smaller and to adopt a spherical shape [67; 96].