Autophagy: cellular and molecular mechanisms

Excerpt:

Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens.

My comment: Autophagy is energy-dependent

See for example: Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Conclusion:

 …TET may represent a conduit through which alterations in this ion are signaled to the genome. Moreover, the observation that RA signaling enhances TET2 expression could be relevant for the treatment of certain cancers. TET2 is a well-described tumor suppressor that is regularly mutated in a number of hematopoietic malignancies (46). Acute promyelocytic leukemia (APL) is a form of myeloid malignancy characterized by PML-RARα translocation and sensitivity to RA treatment, such that RA used in combination with arsenic trioxide can provide a 5-year event-free survival rate of >90% (47, 48), a dramatic improvement for what was once considered the deadliest form of acute leukemia. Nevertheless, a significant number of patients are resistant to RA treatment. A recent analysis found that 4.5% of patients with APL have mutations in TET2, and that a mutation in this and other epigenetic modifiers is a significant indicator of poor disease outcome (49). Our work provides a potential mechanistic explanation for RA insensitivity in patients with APL with TET2 mutations, and if proven in further experimentation, could affect the management of this disease.

Reported as: Vitamins A and C help erase cell memory

Excerpt:

The family of enzymes responsible for active removal of the methyl tags are called TET. The researchers looked at the molecular signals that control TET activity to understand more about how the activity of the TET enzymes can be manipulated during cellular programming to achieve pluripotency.

They found that vitamin A enhances epigenetic memory erasure in naïve ESC by increasing the amount of TET enzymes in the cell, meaning greater removal of methyl tags from the C letters of the DNA sequence. In contrast, they found that vitamin C boosted the activity of the TET enzymes by regenerating a co-factor required for effective action.

My comment: Enzymes do not automagically create themselves for use in links from metabolic networks to genetic networks. The de novo creation of enzymes is energy-dependent and it must link energy-dependent changes from angstroms to ecosystems via biophysically constrained RNA-mediated protein folding chemistry in the context of autophagy.

See for instance: Kohl, James V. (2014): Nutrient-dependent pheromone-controlled ecological adaptations: from atoms to ecosystems.

Excerpt:

…the conserved molecular mechanisms of nutrient-dependent organizing base pair changes are attributed to the epigenetic effects of food odors and the pheromone-controlled physiology of reproduction (J. V. Kohl, 2012). Indeed, methylation of the carbon-5 position of cytosine, which results in differences in 5hmCs, may be the most commonly studied type of nutrient-dependent pheromone-controlled structural and functional eukaryotic modification that results from organizing base pair changes.

Because vitamin C and other vitamins appear to epigenetically effect nutrient-dependent methylation at the level of single-base resolution in mammals, it has become more important to determine how base-pair changes alter intracellular interactions in embryonic stem cells or intercellular interactions in other cells that result in cascades of downstream intracellular and intercellular organizing interactions throughout life. Other vitamins, such as vitamin D, and metal ions such as calcium, iron, lead and manganese also appear to epigenetically alter these organizing interactions. Therefore, a biophysically constrained, nutrient-dependent, epigenetically-effected, receptor-mediated recognizable organized pattern of emergence can be viewed in the context of ecological variations and ecological adaptations.

My comment: For example, lead and manganese containing leaves were linked to the changes in peppered moths that were reported in the context of mutation-driven evolution and selection against predation. Serious scientists know that all organized patterns of emergence must also be viewed in the context of virus-driven energy theft that prevents recognition of any pattern of biophysically constrained cell type differentiation.

Virus-driven energy theft is linked only to patterns of mutations, which are linked to all pathology by the failure of cells to differentiate. Only differentiated cells can be linked to biodiversity in all living genera via the physiology of energy-dependent reproduction. In the peppered moth and all other invertebrates and vertebrates the nutrient-dependent pheromone-controlled physiology of reproduction is linked from autophagy to supercoiled DNA, which protects all organized genomes from virus-driven energy theft.

See also: Pheromone-controlled autophagy

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