What is the mechanism by which aminoglycoside antibiotics (such as streptomycin and gentamicin) damage the mechano-sensory hair cells of the auditory and vestibular system? (Could this be seen as evidence for Lynn Margulis' theory that these cilia are descended from bacteria?)
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1$\begingroup$ Thanks, I added two links (but it doesn't allow new users to add more). Maybe it will let me add another one here: ncbi.nlm.nih.gov/pmc/articles/PMC2728278 $\endgroup$– user6760May 18, 2014 at 0:31
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1$\begingroup$ The article does describe the mechanism. I just didn't know if it is similar to the way it affects gram negative bacteria? "When exposed to aminoglycosides, hair cells demonstrate both morphologic and molecular features of apoptotic cell death, including condensed, marginated chromatin, and positive terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining (Forge and Fradis 1985; Li et al. 1995; Lang and Liu 1997; Nakagawa et al. 1998; Forge and Li 2000; Matsui et al. 2002; Mangiardi et al. 2004)." $\endgroup$– user6760May 18, 2014 at 0:49
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2$\begingroup$ "In addition, aminoglycoside-induced hair cell apoptosis is mediated by c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family...Furthermore, aminoglycoside exposure results in cytochrome c release from the mitochondria and caspase activation in hair cells (Cheng et al. 2002; Cunningham et al. 2002; Matsui et al. 2004; Sugahara et al. 2006)." $\endgroup$– user6760May 18, 2014 at 0:52
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1 Answer
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This phenomenon is called Ototoxicity, which literally means "toxic for the ear". Mostly the cochlea or the auditory nerve are affected and almost all these cases are connected to medications as gentamicin or cisplatin.
The reasons for this are that the cells are either driven into apoptosis or necrosis. This is caused by destroying mitochondria and releasing calcium and cytochrome c which triggers apoptosis or by deregulating the the JNK-signal transduction pathway and causing necrosis. This image gives a nice overview:
For further reading you can start with the Wikipedia page on ototoxicity and then also read these two papers which are both freely available (the figure above is from the first):
- Intracellular mechanisms of aminoglycoside-induced cytotoxicity.
- Gentamicin rapidly inhibits mitochondrial metabolism in high-frequency cochlear outer hair cells.
To answer the question why this occurs in the ear, it seems that there is some genetic predisposition for this, see this paper: "Aminoglycoside-induced ototoxicity." Mitochondrial damages leading to hearing loss is also not uncommin, see here. Noise seems to play an additional role here and is probably the "last drop" to cause hearing loss.
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$\begingroup$ Thank you for your very clear answer and great references! One thing that I still don't quite understand is why the hair cells would be disproportionately affected. Don't all cells contain mitochondria? And if so why isn't apoptosis triggered in all cells? $\endgroup$– user6760May 22, 2014 at 0:20
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$\begingroup$ Thats a good question for which I have no answer at the moment. I will look into it. $\endgroup$– Chris ♦May 22, 2014 at 7:26
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$\begingroup$ It seems that there is some genetic predisposition for this, see this paper: Aminoglycoside-induced ototoxicity. $\endgroup$– Chris ♦May 22, 2014 at 7:35