Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity
(2021) In International Journal of Molecular Sciences 22(1).- Abstract
Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mito-chondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118.... (More)
Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mito-chondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.
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- author
- Avram, Vlad F. LU ; Chamkha, Imen LU ; Åsander-Frostner, Eleonor LU ; Ehinger, Johannes K. LU ; Timar, Romulus Z. ; Hansson, Magnus J. LU ; Muntean, Danina M. and Elmér, Eskil LU
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Cell-permeable succinate, HepG2 cells, Mitochondria, NV118, Platelets, Statins
- in
- International Journal of Molecular Sciences
- volume
- 22
- issue
- 1
- article number
- 424
- pages
- 15 pages
- publisher
- MDPI AG
- external identifiers
-
- scopus:85099052782
- pmid:33401621
- ISSN
- 1661-6596
- DOI
- 10.3390/ijms22010424
- project
- Mitochondrial dysfunction in drug and chemical toxicity: mechanism, target identification and therapeutic development
- language
- English
- LU publication?
- yes
- id
- 97360d09-e4d1-49e3-b468-e65d39dde5a3
- date added to LUP
- 2021-01-20 09:51:19
- date last changed
- 2024-09-19 15:05:20
@article{97360d09-e4d1-49e3-b468-e65d39dde5a3, abstract = {{<p>Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mito-chondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.</p>}}, author = {{Avram, Vlad F. and Chamkha, Imen and Åsander-Frostner, Eleonor and Ehinger, Johannes K. and Timar, Romulus Z. and Hansson, Magnus J. and Muntean, Danina M. and Elmér, Eskil}}, issn = {{1661-6596}}, keywords = {{Cell-permeable succinate; HepG2 cells; Mitochondria; NV118; Platelets; Statins}}, language = {{eng}}, number = {{1}}, publisher = {{MDPI AG}}, series = {{International Journal of Molecular Sciences}}, title = {{Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity}}, url = {{http://dx.doi.org/10.3390/ijms22010424}}, doi = {{10.3390/ijms22010424}}, volume = {{22}}, year = {{2021}}, }