There is a variant of MTHFD1L (rs11754661) that you mention in a genetic lifehacks article on depression as a source of rumination, and I am homozygous (AA), which is pretty rare for that polymorphism. Because of that, I did a deep dive into it, and I believe I was able to trace its biggest impact back to serine, which might be of interest to you in this context. That SNP has also turned up in GWAS for alzheimer’s, by the way. Here is my understanding of how that polymorphism relates to serine. The rs11754661 A allele appears to reduce activity of the MTHFD1L enzyme, reducing the rate at which 1-carbon-units can be extracted from serine or glycine, since it catalyzes the final step in the mitochondrial pathway to produce formate. The "workaround" is to shift more of the burden to the cytosol, which does not have the ability to extract 1-carbon units from glycine, only serine, since there is no glycine cleavage system in the cytosol. The end result, I believe, is that it forces your cells to synthesize serine through glycolysis even when there is glycine available that could otherwise be used in the mitochondrial pathway. Another way to look at it is that one molecule of pyruvate can produce one molecule of serine, which has two carbons that can be extracted in the folate cycle. But if demand for 1-carbon-units is high, the mitochondrial pathway gets backed up. The cytosolic pathway can only get one carbon from each serine, and therefore demands twice as much pyruvate be converted to serine. I think the end result is an excess of glycine, and not enough lactate, or ATP, or D-serine, or whatever else the pyruvate could have been used for. So when demand for 1-carbon-units is high, the cytosolic pathway is like the afterburners of a jet engine, an expensive way to boost output. And for people with the A allele of rs11754661, their astrocytes or other cells may need to use their “afterburners” more than most people. I don't know all the consequences, but this article on serine made me think about that rabbit hole I went down after I read your article "Depression, genetics, and mitochondrial function" on genetic lifehacks. 😄 (thank you for these articles, I really enjoy them!)
There is a variant of MTHFD1L (rs11754661) that you mention in a genetic lifehacks article on depression as a source of rumination, and I am homozygous (AA), which is pretty rare for that polymorphism. Because of that, I did a deep dive into it, and I believe I was able to trace its biggest impact back to serine, which might be of interest to you in this context. That SNP has also turned up in GWAS for alzheimer’s, by the way. Here is my understanding of how that polymorphism relates to serine. The rs11754661 A allele appears to reduce activity of the MTHFD1L enzyme, reducing the rate at which 1-carbon-units can be extracted from serine or glycine, since it catalyzes the final step in the mitochondrial pathway to produce formate. The "workaround" is to shift more of the burden to the cytosol, which does not have the ability to extract 1-carbon units from glycine, only serine, since there is no glycine cleavage system in the cytosol. The end result, I believe, is that it forces your cells to synthesize serine through glycolysis even when there is glycine available that could otherwise be used in the mitochondrial pathway. Another way to look at it is that one molecule of pyruvate can produce one molecule of serine, which has two carbons that can be extracted in the folate cycle. But if demand for 1-carbon-units is high, the mitochondrial pathway gets backed up. The cytosolic pathway can only get one carbon from each serine, and therefore demands twice as much pyruvate be converted to serine. I think the end result is an excess of glycine, and not enough lactate, or ATP, or D-serine, or whatever else the pyruvate could have been used for. So when demand for 1-carbon-units is high, the cytosolic pathway is like the afterburners of a jet engine, an expensive way to boost output. And for people with the A allele of rs11754661, their astrocytes or other cells may need to use their “afterburners” more than most people. I don't know all the consequences, but this article on serine made me think about that rabbit hole I went down after I read your article "Depression, genetics, and mitochondrial function" on genetic lifehacks. 😄 (thank you for these articles, I really enjoy them!)