Complex I inhibitor
Mitochondrial complex I inhibitor
- Energetic stress → activates AMPK
- ↑ insulin sensitivity of body tissues
- ↓ fat accumulation
- ↑ mitochondrial biogenesis
- ↓ hepatic gluconeogenesis
- Excess inhibition impairs oxidative phosphorylation → lactate accumulation
- Example of hormesis
- low doses of a stressor stimulate beneficial adaptive responses, while higher doses are harmful
- Mechanistically related drugs
- Hypoglycemia in ~10% of cases
- Survival is common with aggressive support (IV fluids, hemodialysis)
Drugs with this mechanism (2)
- Metformin — First-line diabetes drug; weight-neutral, sometimes used for antipsychotic weight gain.
- Metformin ER — Extended-release biguanide; often rescues GI intolerance to immediate-release therapy.
Self-check
- How does complex I inhibition affect hepatic gluconeogenesis?
Decreases it. - What accumulates when excessive complex I inhibition impairs oxidative phosphorylation?
Lactate.
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