Subcellular compartmentation of ascorbate and epigenetics
The main goal of our work is to prove the epigenetic effects of ascorbate in two different model systems. The disorganization of extracellular matrix in two different connective tissue disorders - scurvy (caused by general lack of ascorbate) and arterial tortuosity syndrome (accompanied by a local - mainly nuclear - ascorbate deficiency) are similar to those found in aging. Ascorbate – probably via the TGFβ pathway – may play a role in the disintegration of extracellular matrix found in aging, so its function in our model systems can be easily studied. Both our unpublished data and the literature suggest that these effects of ascorbate may be explained by its epigenetic role. Therefore, we plan to examine the mechanistic connections between ascorbate deficiency and extracellular matrix disorganization; we are going to study the level of ascorbate in each subcellular compartment in our aging models. We also plan to analyze the DNA and histone hypermethlyation in general and the methylation state of the presumably affected genes of pathways or enzymes (for example, TGFβ).
The expected results may enlighten the exact mechanism how aging devastate the extracellular matrix and may give bases for therapeutic interventions. Our results will also help to obtain clear picture about the amount and distribution of intracellular ascorbate. Besides, we may describe firstly a disease caused by disruption of ascorbate compartmentation.
Éva Margittai - Péter Lőw