Can Sulfur Save Your Brain?
Here is a conversation starter for your next party:
You: “I was reading that sulfur compounds may protect against some brain diseases by inhibiting ferroptosis”.
Depending on the background of your conversation partner, they might respond with one of the following:
(1) Huh?
(2) Sure, ferroptosis is a recently discovered type of cell death driving some types of neurodegeneration. Are you referring to the glutathione-GPX4 axis?
If their response is (1), you could let them know that some degenerative brain diseases appear to be caused by increased ferroptosis, as I described in a recent article:
Ferroptosis of Microglia Drives Neurodegeneration
This alone may be interesting enough to stimulate a great conversation.
However, if they respond with (2), you are ready. You say:
“Actually, there is a new axis involving sulfur compounds independent of GPX4. These are called sulfane sulfur compounds such as hydropersulfides, and they are great inhibitors of ferroptosis, independent of GPX4!
Ferroptosis and Brain Diseases
Let’s start at the beginning. During degenerative diseases, such as Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, and ALS, certain neurons become damaged and die, leading to these devastating and incurable illnesses. Accumulating evidence suggests that at least some of these diseases, as well as other degenerative processes, are caused by ferroptosis.
Ferroptosis is a form of iron-dependent (hence the name) cell death that was discovered in my lab in 2012 in this paper, and in parallel genetic studies in Marcus Conrad’s lab:
The Glutathione-GPX4 Axis
My lab’s early studies showed that the main process cells use to protect themselves against ferroptosis is the glutathione-GPX4 axis. Glutathione is used by the lipid repair enzyme GPX4 to eliminate lipid hydroperoxides, which are membrane oxidation damage products and drivers of ferroptosis.
Glutathione is built from the amino acid cysteine, which is the primary provider of the element sulfur in cells. We’ve known that cysteine helps prevent ferroptosis, but assumed that was because cysteine is needed to build glutathione, which is needed for the GPX4 repair process that eliminates membrane oxidation damage during ferroptosis.
Enter the New Sulfur Players: Hydropersulfides
In two new papers, the labs of Derek Pratt and Tobias Dick and their colleagues and collaborators showed that cysteine has another way to prevent ferroptosis independent of GPX4:
Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals — PubMed
Hydropersulfides Inhibit Lipid Peroxidation and Protect Cells from Ferroptosis — PubMed
And there is a helpful commentary by James Olzmann here:
Hydropersulfides are endogenous antioxidants that inhibit ferroptosis — PubMed
The Pratt and Dick labs found that cysteine can generate those sulfane sulfur compounds I mentioned at the outset, such as glutathione hydropersufide, which we abbreviate as GSSH. This compound has two adjacent sulfur atoms, hence the abbreviation GSSH.
The Recent Discovery
The new papers show that GSSH and other hydropersulfides such as cysteine hydropersulfide (CSSH) are effective inhibitors of ferroptosis by blocking the chain reactions that damage membranes during ferroptosis. Hence, cysteine is particularly important for suppressing ferroptosis, even independent of GPX4. These new papers open up a number of exciting avenues to see in which tissues and cells these hydropersufides normally function to block ferroptosis, and whether it is possible to augment the amounts of these sulfane sulfur species to treat degenerative diseases involving ferroptosis.
Slaying your Next Party Conversation
Gen Z’ers: is that correct usage?
Getting back to your next conversation, if you find that your conversation partner is already familiar with ferroptosis and has remarkably already heard how hydropersulfides can suppress ferroptosis, you’ve got more one more trick up your sleeve:
You: “Are you familiar with the 21st amino acid?”
Them: “I thought there were only 20 amino acids.”
You: “Selenocysteine is the 21st amino acid, which has a selenium in place of the normal sulfur in cysteine.”
Them: “Wow, I didn’t know there was a 21st amino acid.”
You: “Actually it looks like cysteine hydropersulfide (CSSH) is the 22nd amino acid. The extra sulfur atom in CSSH confers unique properties on this derivative of cysteine and is even inserted into some proteins!”
If you want to learn more, here is a nice review:
