Increase, Oxidative Stress leads to Increase, Mt Dysfunction

Oxidative stress is a cellular state in which there is excess generation of reactive oxygen species (ROS) and oxidation of macromolecules (Guo et al., 2013). The oxidation of macromolecules in particular can lead to many sources of mitochondrial dysfunction, such as the peroxidation of proteins essential to calcium homeostasis within the cell, dysfunction of the mitochondrial permeability transition pore (mPTP), altered mitochondrial membrane potential, and changes in antioxidant gene expression (Kruidering et al., 1997; Belyaeva et al., 2012; Guo et al., 2013).

One modulating factor for the relationship between oxidative stress and mitochondrial dysfunction is age. Many sources have confirmed that mitochondrial ROS production is increased as a result of the mitohormesis hypothesis (Nissanka and Moraes, 2018; Zelenka, Dvorak, and Alan, 2015; Wei et al., 2015; Kudryavtseva et al., 2016). This theory explains that as organisms undergo cellular stresses, ROS are employed as signalling molecules for the stress response pathway (Nissanka and Moraes, 2018; Zelenka, Dvorak, and Alan, 2015; Wei et al., 2015; Kudryavtseva et al., 2016). However, as cells age, they eventually reach a threshhold of age-dependant damage whereupon ROS signalling would become chronic and would lead to mitochondrial dysfunction (Nissanka and Morans, 2018; Zelenka, Dvorak, and Alan, 2015; Wei et al., 2015; Kudryavtseva et al., 2016).

Another known modulating factor between oxidative stress and mitochondrial dysfunction is diabetes. Several studies show that mitochondrial ROS generation, mitochondrial calcium accumulation leading to mitochondrial swelling, and the opening of the mitochondrial permeability transition pore are increased in renal mitochondria from diabetic cases compared to non-diabetic renal mitochondria, and result in a quicker progression from oxidative stress to mitochondrial dysfunction (Forbes and Thorburn, 2018; Schiffer and Friederich-Persson, 2017). Diabetes causes changes in ROS generation due to the fact that cellular hyperglycemia induces increased pyruvate concentrations in the mitochondria (Forbes and Thorburn, 2018; Schiffer and Friederich-Persson, 2017). When pyruvate is used too quickly to supply the ETC with electrons the mitochondrial membrane becomes hyperpolarized and there is a resulting increase in ROS production (Schiffer and Friederich-Persson, 2017). Excessive nutrients in the cell also results in an increased need for insulin production that affects the endoplasmic reticulum (ER).because a large number of sulfide bonds must be formed to create insulin molecules and these reactions increase ROS production as a byproduct (Patergnani et al., 2021). This causes ER dysfunction and impaired protein folding, leading to a vicious cycle of mitochondrial stress leading to ER stress which leads to further mitochondrial stress, eventually inducing apoptosis. The hyperglycemic state of the cells also becomes chronic, leading to the further development of diabetes . These increases in oxidative stress are thereby able to induce heightened mitochondrial dysfunction at a faster rate than in a non-diabetic cell (Patergnani et al., 2021).

Similarly, high fat diets (HFD) have been known to induce renal dysfunction through mitochondrial dysfunction and oxidative stress (Sun et al., 2020). HFD-fed mice developed oxidative stress and mitochondrial dysfunction as a result of the upregulated expression of Gp91, a subunit of NADPH oxidase that is commonly identified as a marker of oxidative stress . Mitochondria were also more numerous in the HFD-fed mice and were releasing increased cytochrome c content, indicating that mitochondrial dysfunction was present and that it was initiating apoptosis (Sun et al., 2020).

The domain of applicability pertains to only eukaryotic organisms, as prokaryotic organisms do not have mitochondria (Lynch and Marinov, 2017).