Complex II phosphorylation is triggered by unbalanced redox homeostasis in cells lacking complex III

Concetta Valentina Tropeano, Jessica Fiori, Valerio Carelli, Leonardo Caporali, Fevzi Daldal, Anna Maria Ghelli, Michela Rugolo

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 languageEnglish
Pages (from-to)182-190
Number of pages9
JournalBiochimica et Biophysica Acta - Bioenergetics
Volume1859
Issue number3
DOIs
Publication statusPublished - Mar 1 2018

Fingerprint

Phosphorylation
Electron Transport Complex III
Oxidation-Reduction
Homeostasis
Tyrosine
Bearings (structural)
Antioxidants
Fumarates
Acetylcysteine
Succinic Acid
Glycolysis
Hydrogen Peroxide
Up-Regulation
Electrons
Mutation
Enzymes

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 journalArticle

Tropeano, Concetta Valentina ; Fiori, Jessica ; Carelli, Valerio ; Caporali, Leonardo ; Daldal, Fevzi ; Ghelli, Anna Maria ; Rugolo, Michela. / Complex II phosphorylation is triggered by unbalanced redox homeostasis in cells lacking complex III. In: Biochimica et Biophysica Acta - Bioenergetics. 2018 ; Vol. 1859, No. 3. pp. 182-190.
@article{f83b6401ebf848469c7d4e6169b54248,
title = "Complex II phosphorylation is triggered by unbalanced redox homeostasis in cells lacking complex III",
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.",
keywords = "Complex III dysfunction, Cytochrome b, Mitochondria, MTCYB gene mutation, Respiratory complex II, Succinate",
author = "Tropeano, {Concetta Valentina} and Jessica Fiori and Valerio Carelli and Leonardo Caporali and Fevzi Daldal and Ghelli, {Anna Maria} and Michela Rugolo",
note = "Pubblicato CORRIGENDUM per modifica di affiliazione (inserito nel pdf della pubblicazione qui allegato). Ricercatore distaccato presso IRCCS a seguito Convenzione esclusiva con Universit{\`a} di Bologna (Carelli Valerio).",
year = "2018",
month = "3",
day = "1",
doi = "10.1016/j.bbabio.2017.12.003",
language = "English",
volume = "1859",
pages = "182--190",
journal = "Biochimica et Biophysica Acta - Bioenergetics",
issn = "0005-2728",
publisher = "Elsevier",
number = "3",

}

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 -