Abstract
A marked stimulation of complex II enzymatic activity was detected in cybrids bearing a homoplasmic MTCYB microdeletion causing disruption of both the activity and the assembly of complex III, but not in cybrids harbouring another MTCYB mutation affecting only the complex III activity. Moreover, complex II stimulation was associated with SDHA subunit tyrosine phosphorylation. Despite the lack of detectable hydrogen peroxide production, up-regulation of the levels of mitochondrial antioxidant defenses revealed a significant redox unbalance. This effect was also supported by the finding that treatment with N-acetylcysteine dampened the complex II stimulation, SDHA subunit tyrosine phosphorylation, and levels of antioxidant enzymes. In the absence of complex III, the cellular amount of succinate, but not fumarate, was markedly increased, indicating that enhanced activity of complex II is hampered due to the blockage of respiratory electron flow. Thus, we propose that complex II phosphorylation and stimulation of its activity represent a molecular mechanism triggered by perturbation of mitochondrial redox homeostasis due to severe dysfunction of respiratory complexes. Depending on the site and nature of the damage, complex II stimulation can either bypass the energetic deficit as an efficient compensatory mechanism, or be ineffectual, leaving cells to rely on glycolysis for survival.
| Original language | English |
|---|---|
| Pages (from-to) | 182-190 |
| Number of pages | 9 |
| Journal | Biochimica et Biophysica Acta - Bioenergetics |
| Volume | 1859 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 1 2018 |
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Keywords
- Complex III dysfunction
- Cytochrome b
- Mitochondria
- MTCYB gene mutation
- Respiratory complex II
- Succinate
ASJC Scopus subject areas
- Biophysics
- Biochemistry
- Cell Biology
Cite this
Complex II phosphorylation is triggered by unbalanced redox homeostasis in cells lacking complex III. / Tropeano, Concetta Valentina; Fiori, Jessica; Carelli, Valerio; Caporali, Leonardo; Daldal, Fevzi; Ghelli, Anna Maria; Rugolo, Michela.
In: Biochimica et Biophysica Acta - Bioenergetics, Vol. 1859, No. 3, 01.03.2018, p. 182-190.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Complex II phosphorylation is triggered by unbalanced redox homeostasis in cells lacking complex III
AU - Tropeano, Concetta Valentina
AU - Fiori, Jessica
AU - Carelli, Valerio
AU - Caporali, Leonardo
AU - Daldal, Fevzi
AU - Ghelli, Anna Maria
AU - Rugolo, Michela
N1 - Pubblicato CORRIGENDUM per modifica di affiliazione (inserito nel pdf della pubblicazione qui allegato). Ricercatore distaccato presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (Carelli Valerio).
PY - 2018/3/1
Y1 - 2018/3/1
N2 - A marked stimulation of complex II enzymatic activity was detected in cybrids bearing a homoplasmic MTCYB microdeletion causing disruption of both the activity and the assembly of complex III, but not in cybrids harbouring another MTCYB mutation affecting only the complex III activity. Moreover, complex II stimulation was associated with SDHA subunit tyrosine phosphorylation. Despite the lack of detectable hydrogen peroxide production, up-regulation of the levels of mitochondrial antioxidant defenses revealed a significant redox unbalance. This effect was also supported by the finding that treatment with N-acetylcysteine dampened the complex II stimulation, SDHA subunit tyrosine phosphorylation, and levels of antioxidant enzymes. In the absence of complex III, the cellular amount of succinate, but not fumarate, was markedly increased, indicating that enhanced activity of complex II is hampered due to the blockage of respiratory electron flow. Thus, we propose that complex II phosphorylation and stimulation of its activity represent a molecular mechanism triggered by perturbation of mitochondrial redox homeostasis due to severe dysfunction of respiratory complexes. Depending on the site and nature of the damage, complex II stimulation can either bypass the energetic deficit as an efficient compensatory mechanism, or be ineffectual, leaving cells to rely on glycolysis for survival.
AB - A marked stimulation of complex II enzymatic activity was detected in cybrids bearing a homoplasmic MTCYB microdeletion causing disruption of both the activity and the assembly of complex III, but not in cybrids harbouring another MTCYB mutation affecting only the complex III activity. Moreover, complex II stimulation was associated with SDHA subunit tyrosine phosphorylation. Despite the lack of detectable hydrogen peroxide production, up-regulation of the levels of mitochondrial antioxidant defenses revealed a significant redox unbalance. This effect was also supported by the finding that treatment with N-acetylcysteine dampened the complex II stimulation, SDHA subunit tyrosine phosphorylation, and levels of antioxidant enzymes. In the absence of complex III, the cellular amount of succinate, but not fumarate, was markedly increased, indicating that enhanced activity of complex II is hampered due to the blockage of respiratory electron flow. Thus, we propose that complex II phosphorylation and stimulation of its activity represent a molecular mechanism triggered by perturbation of mitochondrial redox homeostasis due to severe dysfunction of respiratory complexes. Depending on the site and nature of the damage, complex II stimulation can either bypass the energetic deficit as an efficient compensatory mechanism, or be ineffectual, leaving cells to rely on glycolysis for survival.
KW - Complex III dysfunction
KW - Cytochrome b
KW - Mitochondria
KW - MTCYB gene mutation
KW - Respiratory complex II
KW - Succinate
UR - http://www.scopus.com/inward/record.url?scp=85039715621&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85039715621&partnerID=8YFLogxK
U2 - 10.1016/j.bbabio.2017.12.003
DO - 10.1016/j.bbabio.2017.12.003
M3 - Article
C2 - 29269267
AN - SCOPUS:85039715621
VL - 1859
SP - 182
EP - 190
JO - Biochimica et Biophysica Acta - Bioenergetics
JF - Biochimica et Biophysica Acta - Bioenergetics
SN - 0005-2728
IS - 3
ER -