John Hemming's Web Log

These are two lists of reviews looking at mainly acetyl-CoA, but also other acyl-CoAs. They were selected by a search using chatGPT for the first one and Claude for the second one. Some are behind a paywall. My plan is to read through these and draw out conclusions I will separate out the ones which are behind a paywall. Acetyl-CoA: a central metabolite and second messenger (Cell Metab, 2015) Acetyl-CoA and the regulation of metabolism (Trends Biochem Sci, 2015) Spatiotemporal control of acetyl-CoA metabolism in chromatin regulation (Trends Biochem Sci, 2018) Compartmentalised acyl-CoA metabolism and roles in chromatin regulation (Molecular Metabolism, 2020) Should we consider subcellular compartmentalization of metabolism? (Trends Cell Biol, 2019) The multiple facets of acetyl-CoA metabolism: Energetics, biosynthesis, regulation, acylation and inborn errors (Mol Genet Metab, 2023) Molecular targets and small molecules modulating acetyl-CoA metabolism (ACS Pharmacol Transl...

I recently read a paper Ribonucleotide incorporation into mitochondrial DNA drives inflammation which I found very interesting. The reason I found it interesting is perhaps summarised in the first paragraph of the discussion section which I will quote: We demonstrate that increased incorporation of rNTPs into mtDNA during replication leads to the release of mtDNA fragments from mitochondria and proinflammatory signalling. Our results therefore highlight the challenge that the high molar excess of rNTPs relative to dNTPs poses to cells. Although RNase H2 removes incorporated rNMPs from nuclear DNA as part of the ribonucleotide excision repair pathway, this repair mechanism is not present in mitochondria, which are therefore prone to accumulating rNMPs in their genome. Similar to the effect of rNMPs on nuclear DNA replication27,40, due to the inherent reactivity of the 2′-OH group of the ribose ring or collisions with the replication fork, misincorporated rNMPs may cause DNA strand br...

People who study NCD (Non Communicable Diseases) and particularly those that focus on the diseases of aging (which I think include many of the NCDs, but not all of them) have a concept of someone having a biological age as well as a chronological age. This guides things like how frail someone is, how well their cognition works, whether they are at the risk of cancer or diabetes or indeed how they look. Human beings are quite good at judging each other's general health by appearance. That is because the various NCDs tend to correlate with how well the body maintains the skin and when someone is frail it is quite easy to see this by how they move around. Regular readers of my blog will know that I think this is because the genome stops functioning properly as people get older. In essence cells stop producing the right proteins. I provide full details of this hypothesis on this web page https://citrate.science/2025poster/poster2025.html . Various approaches have been used to cal...

I tend to ask chatGPT for a summary of the transcript of videos so that I don't have to spend the time watching them. I have done this for the ALS Scientific Advisory Council from about a month ago which follows (the critique is of chatGPT - my critique is that they don't talk about mitochondria, the closest they come to epigenetics is DNA methylation): International Alliance of ALS/MND Associations Scientific Advisory Council Webinar – Transcript Summary Opening & Housekeeping Jessica Mabe (Programs Coordinator, International Alliance) welcomed attendees and introduced the webinar, noting caption availability (via Zoom chat or QR code) and thanking sponsor Mitsubishi Tanabe Pharma . The Scientific Advisory Council Chair & Moderator: Dr Nicholas Cole (Head of Research, MND Association, UK) Panelists: Dr Kuldip Dave – Vice President of Research, ALS Association (USA) Dr Nadia Sethi – Co‑chair, NE...

I think it is useful to try to identify: a) The most heavily energy using neurons b) The balance in those cells between OxPhos (which produces Reactive Oxygen Species - ROS) and Glycolysis I will be using various LLMs to search for information relating to this and will be spending time checking the responses for hallucinations, but I may not at the time of you reading this page finished validating everything. I will also be concentrating on validating the analysis for dopaminergic and motor neurons because those are the neurons which cause PD and ALS/MND. In principle the rank is not really valid. Although this table is produced using a ranking that is not going to be reliable, it is still useful. What I am trying to get from this is to identify the cells which would be vulnerable to rapid deterioration through ROS. The first step is those with a high energy usage. This, however, I would expect to vary from time to time and any actual accurate calculation for one human being ...

Regular readers of my blog will have seen that I think there is solid evidence that some neurodegenerative diseases such as ALS (MND) and Parkinsons are caused by a deterioration of mitochondrial DNA primarily because of damage by free radicals (Reactive Oxygen Species - ROS) in the cells. This gradually causes the cells to fail to produce the right proteins and the cells stop working. I think the reason this happens in ALS (MND) and Parkinson's disease is that the cells that suffer are ones which both have a high energy demand, but also make high use of Oxidative Phosphorylation (OxPhos). Hence the mitochondria generate damaging molecules at higher rate which damages the mitochondria at a higher rate than normal. Cells have systems to deal with this, but once it gets to a certain point the deterioration becomes more rapid. Cells in the Central Nervous System have a supply of melatonin via the CerebroSpinal Fluid (CSF) that helps to resist this, but if there is a shortage for...

Given the links between mtDNA damage, splicing, ALS (MND) and PD, an obvious thing to look at is Multiple Sclerosis. MS is a failure of the myelin sheaf. It has been thought to be as a result of an auto-immnue response, but an alternative perspective would be a failure of homeostasis. I thought I would ask chatGPT to look at both sides of the argument about splicing and this is the response: chatGPT O3 response to question: " what are the arguments for and against multiple sclerosis resulting from aberrant splicing in the production of myelin " The summary result from chatGPT is: Bottom line The case for aberrant splicing in myelin production as a contributor to MS is biologically plausible and experimentally supported, but the case against it being the primary cause remains strong. At present, the weight of population genetics and virology favours a model in which immune dysregulation (often EBV-driven) comes first, with myelin-splice errors acti...