A interesting paper in Nature Structural & Molecular Biology finally reveals how metformin really works inside mitochondria.
It doesn’t shut down energy - it fine-tunes the flow of electrons through complex I🧵
It doesn’t shut down energy - it fine-tunes the flow of electrons through complex I🧵
https://twitter.com/atranscendedman/status/1987866218838049084
Complex I is the engine of the respiratory chain.
It transfers electrons from NADH to coenzyme Q10 (ubiquinone) and pumps protons across the membrane to make ATP - the cell’s energy currency.
It transfers electrons from NADH to coenzyme Q10 (ubiquinone) and pumps protons across the membrane to make ATP - the cell’s energy currency.
For years, it was believed that metformin simply blocks this engine.
But a full block would be toxic - cells would lose energy.
The new study shows a smart mechanism - metformin acts only when the enzyme is open and active.
But a full block would be toxic - cells would lose energy.
The new study shows a smart mechanism - metformin acts only when the enzyme is open and active.
Complex I constantly switches between two shapes
open - ready to accept ubiquinone
closed - transferring electrons and pumping protons
(This cycle happens fast - 100-400 times per second.)
open - ready to accept ubiquinone
closed - transferring electrons and pumping protons
(This cycle happens fast - 100-400 times per second.)
Metformin enters the same channel used by ubiquinone (CoQ10),
but it does not bind to ubiquinone directly.
It can access the channel only in the open state.
When ubiquinone triggers the enzyme to close, metformin gets trapped near the redox site.
but it does not bind to ubiquinone directly.
It can access the channel only in the open state.
When ubiquinone triggers the enzyme to close, metformin gets trapped near the redox site.
That trap doesn’t stop the engine - it just slows it down slightly.
The result - smoother respiration, less ROS, better control of cellular energy balance.
The result - smoother respiration, less ROS, better control of cellular energy balance.
This mild braking activates AMPK - the cell’s energy sensor, switching metabolism into a more efficient, restorative mode.
Metformin lets mitochondria breathe, but not overheat.
Metformin lets mitochondria breathe, but not overheat.
Older biguanides like phenformin or proguanil behave differently.
They are hydrophobic, penetrate the membrane and block the Q channel completely, competing with ubiquinone.
Effective, but dangerous, leading to mitochondrial toxicity and lactic acidosis.
They are hydrophobic, penetrate the membrane and block the Q channel completely, competing with ubiquinone.
Effective, but dangerous, leading to mitochondrial toxicity and lactic acidosis.
So metformin, in contrast, is an intelligent modulator
it acts only in specific conformations
doesn’t compete with ubiquinone
and works with the enzyme’s natural rhythm instead of against it.
it acts only in specific conformations
doesn’t compete with ubiquinone
and works with the enzyme’s natural rhythm instead of against it.
That’s why it has
a wide therapeutic window, stable long-term effects, and protective roles beyond diabetes - in aging, inflammation, even neuroprotection.
a wide therapeutic window, stable long-term effects, and protective roles beyond diabetes - in aging, inflammation, even neuroprotection.
Metformin doesn’t block mitochondria - it teaches them to breathe calmly.
He et al. Hydrophilic metformin and hydrophobic biguanides inhibit mitochondrial complex I by distinct mechanisms. Nature Structural & Molecular Biology 2025. nature.com/articles/s4159…
Metformin’s mild Complex I inhibition increases the AMP/ATP ratio - activates AMPK, which in turn inhibits mTORC, the growth and protein-synthesis hub hijacked by viruses and inflammation.
Through this metabolic chain, metformin indirectly suppresses
viral protein translation, inflammatory cytokine storms, and cellular overactivation that drives post-viral fatigue.
Not a kill switch - but controlled inhibition through energy sensing.
viral protein translation, inflammatory cytokine storms, and cellular overactivation that drives post-viral fatigue.
Not a kill switch - but controlled inhibition through energy sensing.
Thats why combining metformin’s mild mitochondrial brake with CoQ10’s electron buffering could, in theory,
restore metabolic rhythm in long COVID - balancing inhibition and energy recovery.
restore metabolic rhythm in long COVID - balancing inhibition and energy recovery.
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