Anaesthetics disrupt complex I-linked respiration and reverse the ATP synthase

Area of Science:

• Biochemistry
• Neuroscience
• Mitochondrial Physiology

Background:

• The mechanism of volatile general anesthetics remains poorly understood, despite their widespread use.
• Anesthetics lack common structural features, suggesting a physical rather than chemical mode of action.
• Previous research hinted at anaesthetics affecting electron transfer and spin polarization.

Purpose of the Study:

• To investigate the specific effects of volatile anesthetics (isoflurane, sevoflurane) on cellular respiration in Drosophila melanogaster.
• To elucidate the impact of these anesthetics on mitochondrial function, including membrane potential and ATP synthesis.
• To correlate anesthetic-induced respiratory changes with observed anesthetic effects.

Main Methods:

• High-resolution tissue fluorespirometry was employed to measure respiration in Drosophila thoraces.
• Mitochondrial membrane potential was assessed using fluorescent indicators.
• ATP availability was predicted using Magnesium-green fluorescence.
• The effects of ATP synthase inhibition (oligomycin) were evaluated.

Main Results:

• Volatile anesthetics, particularly isoflurane, specifically suppressed complex I-linked respiration.
• Anesthetics increased mitochondrial membrane potential, suggesting ATP synthase reversal and ATP hydrolysis.
• A collapse in ATP availability and increased reactive oxygen species (ROS) flux were observed.
• These physiological changes occurred at anesthetic doses comparable to those inducing anesthesia.

Conclusions:

• Volatile anesthetics disrupt mitochondrial complex I-linked respiration, leading to downstream effects on ATP synthesis and membrane potential.
• The findings provide a mechanistic link between anesthetic action and cellular energy metabolism.
• The specific sensitivity of complex I to anesthetics, while not fully explained, is a key aspect of their action.