Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency.
Despite advanced knowledge on the genetic basis of oxidative phosphorylation-related diseases, the molecular and/or cellular determinants for tissue-specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II deficiency occurring before cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca(2+) signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Δψ(mit)) loss, [ATP] reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca(2+) overload are linked to increased endoplasmic reticulum (ER) Ca(2+) leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca(2+)](mit) is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca(2+)] activated on the one hand a compensatory Ca(2+)-dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca(2+) signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II deficiency.
Mbaya
E
E
INSERM U 807, Paris, F-75015 France.
Oulès
B
B
Caspersen
C
C
Tacine
R
R
Massinet
H
H
Pennuto
M
M
Chrétien
D
D
Munnich
A
A
Rötig
A
A
Rizzuto
R
R
Rutter
G A
GA
Paterlini-Bréchot
P
P
Chami
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D015536:Down-Regulation; D042963:Electron Transport Complex II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004734:Energy Metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D009574:Nitro Compounds / Q000494:pharmacology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
D009574:Nitro Compounds; D011422:Propionates; D011728:Pyridones; D017382:Reactive Oxygen Species; C478189:respiratory complex II; C058278:atpenin A5; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; C015392:3-nitropropionic acid; D002118:Calcium