An Overview of Cell Death: Necrosis and Apoptosis

Cell death, like cell growth, differentiation, and proliferation, is a normal part of cell life activities. There are many factors that cause cell death. The internal cause usually refers to the natural death caused by aging, while the external cause refers to the damage caused to the cell by various factors in the external environment exceeding the strength and threshold of the cell. According to different modes of cell death, it can be divided into two types: necrosis and apoptosis. A comprehensive understanding of the different ways cells can die is necessary to develop effective treatments for diseases like cancer.

Fig. 1 Structural changes of cells undergoing necrosis or apoptosis. (Goodlett C R, et al., 2001)

Overview of Apoptosis

Apoptosis is a highly regulated form of cell death that is essential for many homeostatic and pathological processes. The morphology of apoptosis is characterized by cell membrane blebbing, cell shrinkage, and the formation of apoptotic bodies. Apoptosis is primarily initiated by signals generated within the cell itself. It is an essential part of the cell cycle and is mediated by caspases, enzymes present in all cells. In addition, certain stimuli, such as hypoxia, immune responses, high temperature, and exposure to specific chemicals, can induce apoptosis.

Apoptosis can usually proceed through three different pathways, namely the extrinsic pathway, the intrinsic pathway, and the endoplasmic reticulum (ER) stress-induced pathway. The extrinsic pathway is triggered by ligand binding to transmembrane death receptors, such as tumor necrosis factor receptor 1 (TNFR1) and Fas receptor (FasR). The intrinsic pathway, also known as the mitochondrial pathway, involves the release of cytochrome c from the mitochondria to the cytoplasm in response to cellular stress, where cytochrome c interacts with apoptotic protease activating factor-1 (Apaf-1) to form apoptosomes. In the ER stress pathway, infection, hypoxia, starvation, chemical factors (such as tunicamycin\BrefeldinA), and unsteady changes in the secretion function of the ER result in the accumulation of unfolded or misfolded proteins in the ER, which promotes endoplasmic reticulum stress-induced cell death. An unfolded protein response (UPR) pathway is also initiated when protein misfolding occurs in the ER. Other pathways that induce apoptosis include mitotic disorders (MC) and anoikis.

Significance and Applications

Understanding the mechanisms and characteristics of necrosis and apoptosis is vital for various fields of research and applications.

• Disease research and therapy
  The dysregulation of necrosis and apoptosis processes is associated with numerous diseases. For example, abnormal apoptosis can contribute to autoimmune diseases like AIDS or Crohn's disease, whereas necrosis can result from bacterial or fungal infections. Studying these processes helps in developing targeted therapies and understanding disease mechanisms.
• Drug discovery and toxicology
  Pharmaceutical researchers rely on an in-depth understanding of cell death mechanisms to identify potential drug targets and assess drug toxicity. By studying the effects of compounds on necrosis and apoptosis, scientists can evaluate the safety and efficacy of novel therapeutic agents.
• Cancer biology research
  Cancer is often characterized by dysregulated cell death processes. Understanding the delicate balance between necrosis and apoptosis in cancer cells can provide insights into tumor progression, resistance to treatment, and the development of novel anticancer strategies.