Adenosine monophosphate-activated protein kinase and mitochondrial respiratory-chain complex I (AMPK/Complex I)

The AMPK/mitochondrial respiratory-chain complex I axis is a fundamental metabolic signaling pathway that serves as a primary target for the treatment of metabolic disorders. Mitochondrial complex I, or NADH:ubiquinone oxidoreductase, is the largest component of the electron transport chain and plays a pivotal role in cellular energy production by facilitating the transfer of electrons and the pumping of protons across the inner mitochondrial membrane (Bridges et al., 2014). Pharmacological inhibition of complex I, most notably by the biguanide metformin, results in a transient decrease in ATP production and a subsequent rise in the cellular AMP:ATP ratio. This energetic stress is sensed by adenosine monophosphate-activated protein kinase (AMPK), which undergoes conformational changes and phosphorylation to become active (Hardie et al., 2012). Activated AMPK then orchestrates a systemic metabolic shift, enhancing insulin sensitivity, promoting glucose uptake in skeletal muscle, and suppressing hepatic gluconeogenesis (Rena et al., 2017). Beyond diabetes, this target axis is increasingly studied for its role in inhibiting tumor growth by restricting energy availability and for its potential to modulate aging-related pathways.

Other names

AMPK/NADH:ubiquinone oxidoreductaseComplex I/AMPK axisMitochondrial complex I/AMP-activated protein kinase

Inhibition of mitochondrial respiratory-chain complex I leads to a reduction in ATP synthesis and a concomitant increase in the cellular AMP:ATP ratio, which subsequently activates AMPK to restore energy balance (Bridges et al., 2014; Hardie et al., 2012).