I wonder if an FBXL4 mediated oversensitivity to removing slightly mutated mitochondria could explain that. It appears that FBXL4 loss is deleterious to mitochondrial function - from FBXL4's OMIM page:
Patient muscle homogenates or isolated mitochondria showed variably decreased activities of the mitochondrial respiratory chain complexes as well as decreased mtDNA content. Cultured skin fibroblasts had reduced maximal oxygen consumption rate and increased fragmentation of the mitochondrial network. At least 1 patient cell line studied showed a significant reduction of the mitochondrial membrane potential. These defects could be rescued by expression of wildtype FBXL4 in patient cells. The findings indicated that FBXL4 is necessary for the homeostasis of mitochondrial bioenergetics.
We are already looking at this stuff so whether this effect holds up or not (presumably more subtly than this, if so) it will actually come to light as a matter of time.
I was intending to vomit out my encyclopaedic knowledge of the hodgepodge of mitochondrial findings available to provide context to how we interpret this gene coming up (and expected effects of issues with it) but, really, since we have little that is consistent or replicated I actually think it wouldn't really be good to make any major predictions. tldr is some parts of the above cited phenotype have manifested in different studies but variably between sample types and usually with small effect sizes, hard to draw anything definitive. eg: membrane potential reduction.
What's probably more interesting than going back to what we "
know" about mitochondrial studies in ME/CFS is the sort of orthogonal line of enquiry this invites. As far as I am aware mitophagy hasn't really been looked at in published work on ME/CFS. Instead much of the research involving mitochondria has focused on respiratory activity, sometimes on morphology. While morphology is tricky to interpret from particularly older literature where methods were more subjective, there have actually been generally striking differences reported, and in several tissues. It doesn't come up in the discussion often because of the difficulty of interpretation and age of some of the work. But changes in morphology are very clear, direct consequences of changes in how mitophagy is working so if there's anything to that, it's a point in favour.
Anyway. Looking forwards:
I am actually quite surprised that something like this came up (and pleasantly, because it's plausible and interesting). Mitophagy is an interesting angle and issues with it might make more sense in terms of how I imagine things actually happening. Issues with mitochondrial biogenesis, quality control, dynamics and whatever else can very easily elicit stress signalling responses that could plausibly drive many of the issues we have been recently suspecting here on s4me. A mitophagy issue would match the clinical picture much more than the commonly regurgitated blanket "energy production issue". You can have consequences for sensitivity and activation of immune cells, entanglement with ER issues more generally and the list goes on. It's very fertile ground. And to somebody else who I know will read this, wink wink nudge nudge, I won't steal your thunder.
Not as a plug but as a point of optimism and excitement, our lab is particularly well placed to look at many components of this. We are already doing complementary things and we have some unique means to study these processes that aren't commercially available. Hopefully we can add some clarity to whether there are functional consequences here that align with clinical presentation.
I'm starting to design some projects, not just specifically for this gene and mitochondria, but there's my 2c for anyone that wants the quick summary of where we can go with this particular gene.
Apologies if this isn't clear or organised, I'm unwell today but I couldn't just sleep on today's news.
The point is: mitophagy, and more generally the consequences for a cell should mitochondria be forming or breaking up, being cleaned up or talking to other organelles in a crappy way, is a plausible and compelling line of investigation (in my view moreso than a lot of the mitochondrial ideas that are typically memed to death, usually accompanying vague evocations of "energy" and/or "fatigue" - yes I have also been guilty of this).
