Mitochondrial Damage and Depletion

In the past several years, mitochondrial damage and/or depletion as a mechanism of FQ Toxicity have come to the forefront.  Not only are there numerous research studies documenting this, but here again, the FDA is giving us a major clue by publishing this as a stated fact.   And just as they stated that “Fluoroquinolones have neuromuscular blocking activity”, now they are stating and literally telling us that “Fluoroquinolones have been found to affect mammalian topoisomerase II, especially in mitochondria . . . nalidixic acid and ciprofloxacin caused a loss of mitochondrial DNA (mtDNA).” (see link below) Once again, you can’t get any clearer than that.

 

http://www.myquinstory.info/wp-content/uploads/2014/12/FDA-PN-Memo.pdf  Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Pharmacovigilance Review.  (References provided for mitochondrial toxicity within the document).

And as a result of these findings, there is a petition for yet another Black Box Warning to be placed on the FQ class of drugs regarding mitochondrial toxicity, here:

http://media2.abc15.com/html/pdf/mitochondrialtoxicity.pdf   The Southern Network on Adverse Reactions (SONAR) Citizen’s Petition

 

It’s known that FQ’s indeed do direct genomic damage to mitochondrial DNA, as evidenced by mitochondrial DNA breaks from FQ treated cells.  On the other hand, it’s my opinion that mitochondria are as much or more vulnerable to FQ’s due to indirect damage as well.  The thing to know about mitochondria, is that they have a symbiotic relationship with our cells.  Our cells can’t survive without mitochondria, and our mitochondria cannot survive without our cells.  Each is heavily dependent on the other.  And that means, what happens to one, happens to both.

Mitochondria literally cannot survive outside of our cells on their own anymore.  Much of what mitochondria need to survive and function are literally funneled in from the host cell.  They gave up a lot of their own genome, needed to make these substances, billions of years ago when they gave up their own independence and decided to “hitch a ride” so to speak within other cells.  This makes them much more vulnerable to almost any cellular insult that occurs.  That was the price they paid for a somewhat “cushier life” inside our cells.  When times are good for the host cell –they’re good.  But when times are bad for the host cell– mitochondria will suffer too.

Of course, mammalian host cells can no longer survive without mitochondria anymore either.  So anything that happens to mitochondria, are going to affect the host cells too.  Host cells, too, gave up some of their genome and capabilities for survival over to these little guys, and let them do some of the heavy work of creating lots of energy for the both of them.  You can see the circular downward spiral of both host cell and mitochondria that can occur if something bad happens to either one of them.  This is the negative repercussion of what it means to have a symbiotic relationship.

Using thyroid hormones as an example:  when it comes to thyroid hormones, mitochondria are highly dependent on thyroid hormones for their very existence.  Thyroid hormones are like the “signal” to make more mitochondria.  Thyroid hormone (T3) has a profound effect on mitochondrial biogenesis; without T3, there will be less or no mitochondria.  On the other hand, if mitochondria are damaged or depleted due to some reason other than too little T3, then existing T3 has “nothing to act on”.   You can have all the T3 in the world, but without mitochondria, there won’t be any energy.  Again, you can see the circular downward spiral of both host cell and mitochondria that can occur if either 1)too little or no T3 exists, or 2)too little or no mitochondria exist.

From a clinical perspective, you can see that if you don’t have enough T3, your mitochondria number will decline as well, and you just won’t have enough energy.  This appeared to be the case with me the first time I started taking thyroid hormone in June 2011.   At that time, thyroid hormones, and T3, made a huge difference in clearing up my symptoms and providing energy for me, greatly improving my quality of life.   Presumably, I increased my mitochondrial numbers by taking TH/T3.  However, the second time I started up on thyroid hormone again, in Dec 2014, thyroid hormone helped, but in a much more limited fashion.  This time, I could tell that some underlying pathology had progressed quite a bit in me; that “pushing” the thyroid hormone exacerbated other symptoms, including weakness.  I attributed this to Myasthenia Gravis type symptoms; however, if I’m also experiencing mitochondrial depletion due to genomic damage, this could also account for this phenomenon.

A nice summary of how T3 affects mitochondria is given in the “Introduction” section of this paper here:

http://joe.endocrinology-journals.org/content/192/1/111.long  Triiodothyronine modulates the expression of aquaporin-8 in rat liver mitochondria.  “Triiodothyronine (T3) exerts significant actions on energy metabolism, with mitochondria being a major target for its effects (Soboll 1993). Extensive changes occur in the mitochondrial compartment in response either to thyroid hormone administration or to physiological states modulating thyroid gland activity (e.g. cold exposure, aging, dietary changes; Goglia et al. 1999). Indeed, alterations to the thyroid state of animals have considerable effects on the synthesis (Roodyn 1965, Goglia et al. 1988), the turnover (Gross 1971), and the functional capacity of mitochondrial components. Liver mitochondria from hypothyroid rats have a decreased activity of membrane-associated electron transport enzymes and anion carriers (Paradies et al. 1994), a failure that has been ascribed to a lower expression of their corresponding proteins as well as to changes in the composition of the inner membrane (Soboll et al. 1994, Schonfeld et al. 1997). Thyroid hormones are also known to modulate both shape and metabolic efficiency of mitochondria (Jakovcic et al. 1978, Goglia et al. 1988). However, although marked differences in the shape and the number of the cristae have been reported in the liver mitochondria of rats in different thyroid states (Jakovcic et al. 1978, Goglia et al. 1989), the molecular mechanisms underlying T3 modulation of mitochondrial morphology remain mostly elusive. A clue to understanding such mechanisms relates to the fact that mitochondria are well-behaved osmometers and that their shape is influenced by the movement of water accompanying the net transport of solutes into and out of their matrix (Beavis et al. 1985).”

 

A nice summary of the interrelationship between mitochondria and other hormones in addition to TH’s, is given in this abstract here:

http://link.springer.com/chapter/10.1007/978-3-642-59884-5_19  The Triiodothyronine Mitochondrial Pathway “Numerous data show that mitochondrial activity is hormonally regulated. Besides the influence of α-agonists, glucagon and vasopressin, several studies show that glucocorticoid, thyroid hormone, vitamin D3 and peroxisome proliferators stimulate the activity of this organelle. Interestingly, thyroid hormone, glucocorticoid, peroxisome proliferators and vitamin D3 receptors all belong to a common nuclear receptor superfamily. These data suggest that such receptors could have a particular importance in the regulation of mitochondrial activity.”

 

If you remember that back in “Iodine:  Like T3 in Me”, my own conclusions based on my own experiences with Iodine were that Iodine was essentially acting like T3 in me in all the cells of my body.  I provided some existing study references supporting this controversial conclusion.  Hydrogen Peroxide (H2O2) is normally generated within the thyroid gland as a requirement for the synthesis of thyroid hormone.  Mitochondrial respiration is a source of H2O2 generated as a byproduct.  Interestingly enough, mitochondria may be ideal for creating a source of iodinated proteins, ie, T3 – and may very well be doing so, as this study suggests:

http://www.ncbi.nlm.nih.gov/pubmed/16120321   Uphadhyay, G.  Differential action of iodine on mitochondria from human tumoral- and extra-tumoral tissue in inducing the release of apoptogenic proteins.   Mitochondrion. 2002 Dec;2(3):199-210.  “For achieving the iodination of proteins (my addition:  ie, producing T3), H2O2, iodine and oxidative enzymes are sine qua non (my addition:  absolutely necessary).  The reactive oxygen species (ROS) including H2O2 generated as a byproduct of the electron transport chain and oxidative enzymes embedded in the inner mitochondrial membrane make the mitochondria ideal cellular organelles for the iodination of proteins . . .[our experiments] suggest that iodine is not only concentrated by the mitochondria but is also organified . . .intense iodination in extra-tumoral, (my addition:  ie, normal tissues) indicating parity as in the thyroid tissue . . . [we assessed] whether the iodination of proteins is a result of peroxidase mediated reaction . . . [and] clearly indicated the involvement of peroxidases or similar enzyme system which may mediate the process.”

 

A search of the PubMed database for “fluoroquinolone” + “mitochondria” will bring up related studies.  A good source of information regarding known and suspected relationships between mitochondria and fluoroquinolone induced mitochondrial damage can be found on the FloxieHope website here:

http://floxiehope.com/2014/03/20/your-mighty-mitochondria/

 

Given this potential mechanism of damage for flox victims, I hope more and more flox victims over time can be tested for mitochondrial damage (see Why Test?, and “Dear Doctor” letters).  I hope that tested flox victims can then come together with their test results, to see if there are any commonalities, if any, in genomic or metabolic damage.  It would also be nice to test this against maternal mtDNA if possible, in an effort to determine if these were inherited traits vs. environmental (ie, FQ induced vs unmasked).  Lastly, I think it would be interesting to study any abnormalities against bacterial susceptibility/resistance issues in bacteria exposed to FQ’s, to see if there are any commonalities there.  Such studies, and their interpretations, are probably much more complicated in practice than on paper for a variety of reasons.  But we’re on the cusp of a genomic revolution here, so maybe it’s not as far fetched as it initially seems.

 

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