Methadone induces necrotic-like cell death in SH-SY5Y cells by an impairment of mitochondrial ATP synthesis
Identifiers
URI: http://hdl.handle.net/20.500.12020/1231ISSN: 0925-4439
DOI: 10.1016/J.BBADIS.2010.07.024
Author/s
Perez-Alvarez, Sergio; Cuenca-Lopez, Maria D.; Melero Fernandez de Mera, Raquel Maria; Puerta, Elena; Karachitos, Andonis; [et al.]Date
2010-11Document type
articleMateria/s Unesco
32 Ciencias MédicasAbstract
Methadone is a widely used therapeutic opioid in narcotic addiction and neuropathic pain syndromes.
Oncologists regularly use methadone as a long-lasting analgesic. Recently it has also been proposed as a
promising agent in leukemia therapy, especially when conventional therapies are not effective. Nevertheless,
numerous reports indicate a negative impact on human cognition with chronic exposure to opiates. Thus,
clarification of methadone toxicity is required. In SH-SY5Y cells we found that high concentrations of
methadone were required to induce cell death. Methadone-induced cell death seems to be related to necrotic
processes rather than typical apoptosis. Cell cultures challenged with methadone presented alterations in
mitochondrial outer membrane permeability. A mechanism that involves Bax translocation to the
mitochondria was observed, accompanied with cytochrome c release. Furthermore, no participation of
known protein regulators of apoptosis such as Bcl-XL and p53 was observed. Interestingly, methadone induced cell death took place by a caspases-independent pathway; perhaps due to its ability to induce a
drastic depletion in cellular ATP levels. Therefore, we studied the effect of methadone on isolated rat liver
mitochondria. We observed that methadone caused mitochondrial uncoupling, coinciding with the
ionophoric properties of methadone, but did not cause swelling of the organelles. Overall, the effects
observed for cells in the presence of supratherapeutic doses of methadone may result from a “bioenergetic
crisis.” A decreased level of cellular energy may predispose cells to necrotic-like cell death.