# Structural Biochemistry/Cell Organelles/Mitochondria/Reactive Oxygen Species (ROS)

Reactive Oxygen Species (ROS) are molecules that contain oyxgen. Depending on the levels of ROS, they may either be beneficial are destructive to a cell.

## History

At first, scientists thought that ROS were harmful molecules. The first discovered antioxidant, superoxide dimutase, was found to convert the ROS, superoxide (a toxic molecule), into hydrogen peroxide. This led scientists to believe that ROS are toxic byproducts and must be converted into something harmless. Decades later, cells were found to live solely to produce ROS, causing doubt that ROS is only a harmful molecule.
High ROS levels also correlated with cancer and diabetes. However, ROS was later disproved to be the cause of cancer and diseases with multiple experiments. On the contrary, the antioxidants sometimes even increased mortality rates.

## ROS Production

The main source of ROS in mitochondria is from the electron transport chain. Superoxide is produced when O$_2$ is reduced to O$_2$$^-$. Superoxide dimutases (SODs) then convert the superoxide to hydrogen peroxide. This process can occur with any complexes of the electron transport chain. Complexes I and II can produce ROS into the matrix of the mitochondria while complex III can produce ROS on both sides of the membrane.

## ROS and Hypoxia

Hypoxia is when cells are exposed to low levels of oxygen. During hypoxia, the cell needs to use oxygen and energy more conservatively. In response, the cell creates more ROS. The ROS inhibits prolyl hydroxylases (PHD2), which stabilizes HIF. The stabilized HIF will allow transcription to occur and express genes regulating glycolysis, angiogenesis, and erthropoiesis.
To reduce oxygen consumption, ROS suppresses Na/K-ATPase activity. The production of ROS activates AMP-activated protein kinase (AMPK) to lowers ATP usage in cells. AMPK phosphorylates Na/K-ATPase to cause endocytosis, inhibiting the activity of Na/K-ATPase.
ROS can also helps constrict the pulmonary arteries to redirect oxygen-poor blood to the lungs. Pulmonary artery contraction is caused by the increase of calcium, which is directly dependent to the levels of ROS production.

## FOXO

Forkhead box O (FOXO) is a family of transcription factors that help cell cycle arrest, stress resistance, apoptosis, and tumor suppression. High levels of ROS help cause hypertrophy (cell growth) to allow cardiac cells adapt to stressful environments. However, if hypertrophy lasts too long, the heart may have congestive heart failure and eventually death. As a result, FOXO will activate to scavenge ROS to prevent heart failure. Protein Kinase B (Akt) activation inhibits FOXOs via phosphorylation, allowing ROS to accumulate again if needed.$^{[1]}$

### Proliferation and Differentiation

Experiments have shown that FOXO is needed to regulate ROS levels; otherwise, cell death will occur. Low levels of ROS will allow the cell to differentiate and proliferate; however, ROS production increases as differentiation increases. In hematopoietic stem cells (HSC), deletion of the FOXO 1, 3, and 4 genes disrupts causes hyperproliferation to the cells and eventually death. The HSCs can live, however, if they are treated with antioxidants to combat the high levels of ROS. Similar results may be observed in mice with the deletion of Bmi1.

## Cell Transformation and Cell Death

Tumor necrosis factor alpha (TNFα) helps decide whether a cell lives or dies. The decision depends on kappa-light-chain-enhancer of B cells (NF-κB) activity and the activity of c-Jun N-terminal kinase (JNK). JNK helps signal death for a cell. Without NF-κB, JNK is active longer, causing more cells to die. Without NF-κB, SOD2 does not activate and allows ROS to accumulate. ROS can inactivate JNK phosphatases, leading to prolonged JNK activtity and as a result, more cell death. ROS has been proven to have a role, because treatment with antioxidants without SOD2 present increases cell survival rates.$^{[1]}$
ROS were thought to be the cause of mutation in tumors and cancer cells because ROS levels directly correlated with mutation rates. Also, when a tumor was treated with antioxidants, the tumor growth was inhibited.
ROS actually helps signal tumor suppressors to activate. When oncogenes Ras and Myc are overexpressed, ROS increases and helps transform cells. However, in response to ROS, Sirtuin 3 (SIRT3), a tumor suppressor which activates FOXOs. FOXOs in return decrease ROS levels. The activated tumor suppressor SIRT3 also kills the cells.$^{[1]}$

## Reference

* Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes.
       Hamanaka RB, Chandel NS.
       Trends Biochem Sci. 2010 Sep;35(9):505-13. Epub 2010 Apr 27. Review.
       PMID: 20430626 [PubMed - indexed for MEDLINE] Free PMC Article
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