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Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity

Avram, Vlad F. LU ; Chamkha, Imen LU ; Åsander-Frostner, Eleonor LU orcid ; Ehinger, Johannes K. LU orcid ; Timar, Romulus Z. ; Hansson, Magnus J. LU orcid ; Muntean, Danina M. and Elmér, Eskil LU orcid (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 Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct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
; ; ; ; ; ; and
organization
publishing date
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
2024-07-11 07:24:01
@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}},
}