Hope for genetic disorders — mitochondrial and cell based therapeutic avenues for ehlers danlos syndrome

Ehlers danlos syndrome is agroup of inherited conditions that affect the bodies ability to produce sufficent levels of collagen. Collagen is important for connective tissue, which provides support in skin, tendons, ligaments, blood vessels, internal organs, and bones. Symptoms of EDS can vary but typically include an increased range of joint movement (ioint hypermobility), stretchy or fragile skin that bruises easily, joint pain, and an increases risk of things like aortic dissection, prolapsed and ruptured organs

A lot of people focus on the gene mutations involved in EDS. I drill discuss this a bit but I want to focus on the role of mitochondrial function (and dysfunction which is present in many individuals with EDS and CFS) and it’s role in collagen production as well as therapeutic application for patients with EDS. Particularly because it tends to get ignored.

Collagen synthesis relies heavily on the overall energy status of the cell, which is influenced by mitochondrial function and the electron transport chain. If complex I and complex II of the ETC are shut down, it will significantly impact the cell's ability to produce ATP, as these complexes play crucial roles in the oxidative phosphorylation process, which generates the majority of cellular ATP.

Here's how this impacts collagen synthesis:

Complex I and II are essential for the initial stages of the ETC, where electrons are transferred to coenzyme Q. If these complexes are non-functional, electron flow through the chain will be severely impaired, leading to reduced proton pumping and ATP synthesis. Collagen synthesis is an energy-intensive process, requiring ATP for various stages, including amino acid activation and the post-translational modifications of collagen proteins.

ollagen synthesis also requires the hydroxylation of proline and lysine residues, a process that is catalyzed by prolyl and lysyl hydroxylases. These enzymes require oxygen, iron, and ascorbate (vitamin c ) to function and are dependent on sufficient cellular energy. A compromised ETC reduces ATP availability, affecting the function of these hydroxylases and leading to improper collagen folding and stability.

General protein synthesis, including collagen, is energetically demanding as mentioned. The ribosome assembly, tRNA charging, peptide bond formation, and protein folding all require ATP. With limited ATP, the overall rate of protein synthesis, including that of collagen, would decrease. Dysfunctional ETC components can lead to increased production of free radicals as well, Elevated ROS can damage cellular components, including DNA, proteins, and lipids. Which can further impair the synthesis and proper folding of collagen molecules.

As mentioned, dysfunctional or mutated genes are often talked about and implicated in conditions like EDS. We will be diving deeper into this later. But we can’t forget that EDS patients still produce collagen. If they didn’t produce any, they’d be dead. They’re just not producing *enough* of it. But this this is almost always compounded by the mitochondrial dysfunction described above. It really could be considered inseparable from the other pathological and or molecular manifestations of the disease itself. Rarely do patients with EDS NOT have some form of mitochondrial dysfunction.

patients with EDS have unmet needs and many are told things like diet, lifestyle, and supplements won’t help them. I don’t believe this is true. In order to compensate for a reduce ability to produce collagen, we need to be thinking about mitochondrial and cell based interventions and therapies for patients with EDS. I do believe it may be possible to greatly compensate for this deficit with the aforementioned therapeutic avenues.

From a genetic POV, also consider that some compounds can modulate gene expression through epigenetic mechanisms. For example, certain dietary factors can influence DNA methylation or histone modifications, which can affect how genes are expressed. Hypothetically, specific compoundscould influence the expression of genes involved in collagen production or connective tissue maintenance, possibly mitigating some of the effects of genetic mutations in EDS. So we shouldn’t see these (mitcondrial function and ‘genetics’) as interventionally seperate.

Gene therapy has been a big focus for conditions like EDS, but there are things like bio-regulators (I like to refer to these as ‘pseudo’ gene therapy) that have similar therapeutic mechanisms of action (epigentic regulators). Cartalax and GHK copper are a few that come to mind. These are theoretical treatment avenues but we have seen (no pun intended) this pan out successfully in clinical practice with the use of bio-regulator peptides like retamalanin for rare genetic disorders of the eye like rod cone dystrophy. I have no reason to believe that the connective tissues peptide regulators couldn’t have a similar effect, and I have (ancedotelly) seen this to be the case with two clients I’ve worked with who have EDS. There are also some great studies on hyperbaric oxygen and it’s ability to positively modulate the genome. Particularly genes related to collagen synthesis and repair.