HYPOXIA #20: HOW DOES ANEMIA STIMULATE HYPOXIA AND A LOSS OF GROWTH CONTROL?

Did you know that melanopsin damage in the skin fat eyes or in your arteries is capable of causing anemia?  How could this happen?  Recent research has shown that depletion of mito-Super Oxide Dismutase, which acts as free radical in our mitochondria, inhibited succinate dehydrogenase activity leading to succinate accumulation in our colony of mitochondria.  This also lowers the amount of light hydrogen isotope created from foodstuffs that is needed to reduce NAD+ to NADH at cytochrome one.  The dual act seems to prevent nuclear DNA demethylation and inhibited red blood cell-like maturation from HEL cells.  RBC maturation is a process dependent on DNA demethylation. 

This appears how anemia of chronic disease occurs.   Anemia of chronic disease refers to having low levels of red blood cells as a result of how the presence of chronic diseases  (autoimmune diseases in which the body's immune system attacks joints and/or body organs) or other chronic illnesses associated with low mitochondrial energy production.  People forget the first step of heme synthesis begins in the mitochondrial matrix so any level of mitochondrial damage limits heme synthesis for proteins.  

Two hundred-billion red blood cells are renewed in our body every single day. These erythrocytes (also known as RBCs) are generated from bi-potent megakaryocyte-erythroid progenitor cells during a maturation process called erythropoiesis.  Hypoxia stimulates erythropoiesis.  Erythropoiesis is controlled very tightly and defects in the key elements of this step-wise maturation can lead to life-threatening conditions such as severe anemia or myeloproliferative disease. Transcriptional RNA interference-dependent and translational regulations are part of the core mechanisms required for proper erythropoiesis. Recently, an mRNA modification called N6-methyladenosine (m6A) has been found to control the expansion and self-renewal of hematopoietic stem cells.

In recent years, methylation at the N6 position of adenine (m6A) has gained the attention of RNA biologists because it seems control traffic in protein synthesis inside the cell.  This implies that hypoxia is one of the key environmental signals to increase protein synthesis, mTOR, and uncontrolled growth in cells.  The process of increased protein synthesis is controlled by the process of ubiquitination.  Ubiquitination is controlled by the circadian mechanism in the human body.  This links the amount of nnEMF, blue light exposure, or a lack of sun light to alterations in protein metabolism. 

These are the foundational changes that support cancer generation when there is a chronic hypoxic stress stimulus.  Succinate accumulation in the TCA cycle in the mitochondrial matrix links mitochondrial MnSOD depletion to aberrant nuclear DNA methylation and these processes altered cell fates.  This is how alterations in energy production in mitochondrial causes an altered metabolism and can lead to diseases. 

Succinate accumulation is associated with increased production of reactive oxygen species (ROS) production due to an altered metabolism.  In the brain increased levels of succinate precedes neuronal injury, and plays a critical role in neurologic disease like epilepsy.  Epilepsy is also associated with hypoxia.  

The production of ROS/mitochondrial ROS is associated with defects of mitochondria. For example, the production of ROS may be partly due to a defect in mitochondria that leads to altered energy consumption and energy dyshomeostasis.   There are many sources of mitochondrial ROS, including complex I (NADH dehydrogenase), complex II (succinate dehydrogenase, SDH), and complex III (coenzyme Q-cytochrome C reductase) of the electron transport chain (ETC). 

Related studies have also indicated that the ROS signaling may be mainly derived from reverse electron transport (RET) to the ETC at complex I. Inhibition of complex I of the ETC induces mitochondrial ROS, oxidative damage, and increased neuronal loss 

Messenger RNA is a flexible toolbox that plays a key role in the dynamic regulation of gene expression. RNA modifications variegate the message conveyed by the mRNA. Similar to DNA and histone modifications, mRNA modifications are reversible and play a key role in the regulation of molecular events. 

Many people have asked me how chronic exposure to nnEMF or blue light can lead to cancer and a loss of control of this process is the answer to that question.  

This is why when my members hire me to become their doctor at my Center in Destin their peripheral blood smear is one of the key things I look for that tell me about possible diseases that will be a problem for them in the future is they do not change the environments they allow. 

CITES 

1.       Kuppers DA, Arora S, Lim Y, Lim AR, Carter LM, Corrin PD, Plaisier CL, Basom R, Delrow JJ, Wang S, Hansen He H, Torok-Storb B, Hsieh AC, Paddison PJ. 2019. N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis. Nat Commun. 10(1):4596. doi: 10.1038/s41467-019-12518-6.

2.       Zeng et al. 2018. Refined RIP-seq protocol for epitranscriptome analysis with low input materials. PLoS Biol. 16(9):e2006092. doi: 10.1371/journal.pbio.2006092.

3.       Dominissini et al. 2012. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 485(7397):201-6. doi: 10.1038/nature11112.

4.       Meyer et al. 2012 Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell. 149(7):1635-46. doi: 10.1016/j.cell.2012.05.003.