About the mitochondrial pyruvate carrier in mitochondria

Amazing stuff!

"Scientists ... have worked out the structure of this machine and shown how it operates like the lock on a canal to transport pyruvate – a molecule generated in the body from the breakdown of sugars – into our mitochondria.

Known as the mitochondrial pyruvate carrier, this molecular machine was first proposed to exist in 1971, but it has taken until now for scientists to visualise its structure at the atomic scale using cryo-electron microscopy, a technique used to magnify an image of an object to around 165,000 times its real size.  ...

When [sugars] are broken down inside our cells they produce pyruvate, but to get the most out of this molecule it needs to be transferred inside the cell’s powerhouses, the mitochondria. There, it helps increase 15-fold the energy produced in the form of the cellular fuel ATP.” ...

Using state-of-the-art cryo-electron microscopy, we’ve been able to show not only what this transporter looks like, but exactly how it works. It’s an extremely important process, and understanding it could lead to new treatments for a range of different conditions.

Mitochondria are surrounded by two membranes.

The outer one is porous, and pyruvate can easily pass through, but the 

inner membrane is impermeable to pyruvate.

To transport pyruvate into the mitochondrion, first an outer ‘gate’ of the carrier opens, allowing pyruvate to enter the carrier.

This gate then closes, and the inner gate opens, allowing the molecule to pass through into the mitochondrion. ...

this carrier is now recognised as a promising drug target for a range of conditions, including diabetes, fatty liver disease, Parkinson’s disease, specific cancers, and even hair loss. ..."

From the abstract:

"The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction–associated steatotic liver disease.

We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo–electron microscopy, revealing its alternating access rocker-switch mechanism.

The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions."

Throwing a ‘spanner in the works’ of our cells’ machinery could help fight cancer, fatty liver disease… and hair loss | University of Cambridge "Fifty years since its discovery, scientists have finally worked out how a molecular machine found in mitochondria, the ‘powerhouses’ of our cells, allows us to make the fuel we need from sugars, a process vital to all life on Earth."

Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier (open access)

Fig. 1. Human MPC [mitochondrial pyruvate carrier] in the outward-open and inward-open states.

Fig. 2. The dynamic motions of the MPC.