Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II...

Area of Science:

• Biochemistry
• Cell Biology
• Mitochondrial Biology

Background:

• Oxidative phosphorylation (OXPHOS) diseases have known genetic causes, but tissue-specific dysfunction mechanisms remain unclear.
• Understanding cellular events in mitochondrial respiratory chain deficiencies is crucial for therapeutic development.

Purpose of the Study:

• To elucidate the cellular events and calcium (Ca2+) signaling alterations in mitochondrial Complex II deficiency prior to cell death.
• To investigate the interplay between Complex II deficiency, Ca2+ homeostasis, and cellular energy production.

Main Methods:

• Utilized cell models with Complex II mutation or chronic inhibition.
• Measured cytosolic and mitochondrial Ca2+ signals, membrane potential (Δψ(mit)), ATP levels, and reactive oxygen species (ROS).
• Assessed endoplasmic reticulum (ER) Ca2+ handling, protein degradation (SERCA2b, PMCA), mitochondrial motility, and ER-mitochondria contacts.

Main Results:

• Complex II deficiency led to significant increases in basal and agonist-evoked cytosolic and mitochondrial Ca2+ signals.
• Observed mitochondrial dysfunction, including Δψ(mit) loss, reduced ATP, and increased ROS production.
• Ca2+ overload was linked to ER Ca2+ leakage, SERCA2b/PMCA degradation, altered mitochondrial dynamics, and increased ER-mitochondria contacts.

Conclusions:

• Ca2+ signaling plays a primary role in controlling mitochondrial dysfunction and cellular bioenergetics in Complex II deficiency.
• Increased intracellular Ca2+ has dual effects: activating compensatory glycolysis and exacerbating mitochondrial pathology.
• These findings offer insights into the cellular pathogenesis of OXPHOS disorders.