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cellular dysfunction
Impaired metabolic homeostasis
The purpose of metabolism is to convert nutrients into energy to perform cellular processes, or into building blocks for cellular structures. The majority of nutrients are broken down via glycolysis or beta oxidation to yield acetyl-CoA, which delivers an acetyl group to the citric acid cycle in the mitochondrial matrix. As the acetate and other nutrients are consumed, different coenzymes are activated to capture and transfer energy for ATP production. Several central regulators function to sense nutrient and energy status, and regulate the activity of metabolic enzymes and processes accordingly. However, a constant overabundance of nutrients can lead to deregulation of metabolic homeostasis and downstream defects.
cellular dysfunction
Mitochondrial dysfunction
Energy in the form of ATP is produced as the result of oxidative phosphorylation through the electron transport chain at the inner mitochondrial membrane. As a regular by-product of mitochondrial respiration, leakage of highly reactive free radicals such as superoxide can occur, which causes oxidative deterioration of various macromolecules. Specialized antioxidant defense systems exist to attenuate the damaging effects of reactive oxygen species (ROS). Damage to the mitochondrial DNA may result in mutations or deletions, while damage to mitochondrial proteins and lipids may compromise the particular structure of the mitochondrial membrane, the cristae, which consequently impairs the electron transport chain resulting in increased production of mitochondrial ROS.
cellular dysfunction
Inadequate stress response
Exposure to oxidative, proteotoxic, or genotoxic stress leads to activation of various distinct stress response and repair pathways, such as the antioxidant, proteostasis, or DNA damage repair pathways. Stressors are detected via specific sensors and mediated through factors that activate transcriptional programs to repair damage and restore homeostasis.
Tissue degeneration
Stem cell exhaustion
Stem cells are essential for regeneration as they replenish the tissues of an organism with functional differentiated cells to maintain tissue homeostasis and function. They usually reside in a specific niche in a quiescent state until they get activated by various factors triggering proliferation and self-renewal. Due to their extremely high vulnerability, stem cell regenerative capacity is compromised by a decrease in the number of stem cells, diminished response to activating stimuli, and loss of the ability to differentiate into the correct functional cells.
Tissue degeneration
Disrupted tissue homeostasis
Tissues consist of different types of cells and extracellular matrix that serves as a scaffold for tissue structure. Some tissues consist of highly functional differentiated cells while others have a very fast turnover, where cells constantly proliferate and differentiate. Maintenance of tissue homeostasis requires a balance between cell growth and cell death, which is regulated by cells and stimuli from their environment. Impairment of different cellular processes can cause disruption of the mechanisms for cell growth and death regulation, and result in altered responses to extracellular signals. Excessive growth could trigger tumorigenesis while failure to induce cell death may lead to increased senescence. Such dysfunctional cells are detrimental to other surrounding cells and the extracellular matrix, compromising overall tissue homeostasis.
Tissue degeneration
Altered intercellular signaling
Cells across the entire organism communicate with each other via various signaling mediators, ranging from hormones, growth factors, neurotransmitters and other metabolites to extracellular vesicles filled with a mix of molecules that elicit distinct responses in the target cells. As cellular function and tissue integrity decline, the circulating mediators shift and the response in target cells is distorted which causes further dysregulation.
Molecular Alterations
Genome instability
The genome is organized in chromosomes which carry the information required to build a functional organism, encoded in its DNA. Various stresses, like radiation and free radicals can lead to physical alterations in DNA structure, such as breaks, crosslinks, and other modifications, and several sophisticated mechanisms have evolved to repair such damage. During cell division, a copy of the entire genome is generated and any remaining damage can increase the risk for errors in the DNA replication process. These errors can comprise single point mutations in the genetic code, but also include chromosomal aberrations, transpositions and copy number variation. In addition, the ends of chromosomes are protected by structures called telomeres, which also get damaged and eroded with each cell division.
Molecular Alterations
Epigenetic modifications
Each cell in an organism contains the exact same genome, yet can possess vastly different properties and perform vastly different functions. This is possible because the DNA is coiled around histone proteins into a secondary structure, called chromatin, which serves to condense the genomic DNA and control its transcription. Regulation of chromatin through modifications like DNA methylation or histone acetylation is therefore critical for gene expression, and changes in chromatin structure can result transcriptional defects.
Molecular Alterations
Deregulated macromolecular homeostasis
Once genes are successfully transcribed, the resulting RNA can be modified via alternative splicing to generate multiple protein variants which may have different cellular functions or properties. When RNA is decoded to proteins, translational infidelity promotes protein errors which may result in dysfunctional proteins. Along with defects in protein folding or other damages to the protein structure, protein stress response pathways such as the unfolded protein response or the heat shock response are being activated to initiate refolding or removal of damaged proteins and avoid accumulation of harmful aggregates. Various mechanisms have evolved to degrade dysfunctional macromolecules and organelles, via the ubiquitin proteasome system or the autophagy lysosomal pathway.
