Unwrapping the secrets of sugar metabolism

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Posted:

25 Apr 2025

Ever wondered why eating something sugary gives you such an energy boost? It turns out that the secret lies within our cells, specifically in tiny structures called mitochondria, often dubbed the cell’s ‘powerhouses’.

Fifty years since its discovery, scientists in the laboratory of Trinity Hall Fellow Professor Edmund Kunji have worked out how a molecular machine found in mitochondria allows us to make the fuel we need from sugars, a process vital to all life on Earth. Sugar alone provides relatively little energy when initially processed in the cell, but once its breakdown product, pyruvate, enters the mitochondria, energy production dramatically increases by more than 15-fold.

The researchers at the Medical Research Council (MRC) Mitochondrial Biology Unit in Cambridge have uncovered, for the first time, the precise molecular mechanism of a crucial transport protein that allows our bodies to generate energy efficiently from sugar. This discovery provides fundamental new insights into how human cells produce energy and could pave the way for novel treatments for diseases ranging from diabetes and cancer to neurodegeneration and metabolic disorders.

“Drugs inhibiting the function of the carrier can remodel how mitochondria work, which can be beneficial in certain conditions,” explains Professor Kunji.

“Electron microscopy allows us to visualise exactly how these drugs bind inside the carrier to jam it – a spanner in the works, you could say. This creates new opportunities for structure-based drug design in order to develop better, more targeted drugs. This will be a real game changer.”

In groundbreaking research, the team in Cambridge has now revealed the intricate workings of a protein known as the mitochondrial pyruvate carrier. Acting like a selective canal lock, the carrier transports pyruvate, the cellular breakdown product of sugar, across the mitochondrial membrane, significantly amplifying the production of ATP – the essential cellular fuel that powers almost all of life on Earth.

“It works like the locks on a canal but on the molecular scale,” says Professor Kunji. “There, a gate opens at one end, allowing the boat to enter. It then closes and the gate at the opposite end opens to allow the boat smooth transit through.”

Using advanced cryo-electron microscopy techniques, the scientists were able to visualise the mitochondrial pyruvate carrier in detail, finally explaining observations that had puzzled biologists for more than 50 years. The detailed structure shows how the carrier protein moves pyruvate into mitochondria, providing a glimpse into a process essential for life.

Because of the protein’s fundamental importance in cellular metabolism, scientists believe it could become a prime therapeutic target. Understanding precisely how the mitochondrial pyruvate carrier works enables the design of more effective and specific drugs to treat conditions like diabetes, fatty liver disease, various cancers, and even neurodegenerative diseases.

“Everybody involved in this difficult project has been absolutely amazing, in particular the first authors Max Sichrovsky (Hughes Hall), Denis Lacabanne (St Catharine’s), Jonathan Ruprecht (Fitzwilliam) and Jessica Rana (NIH). We are also grateful to our excellent collaborators Vanessa Leone (Medical College of Wisconsin) and Lucy Forrest (NIH), who provided the computational analysis of the protein’s movements and pyruvate binding, Els Pardon and Jan Steyaert (Free University of Brussels), who provided the crucial Llama nanobodies that made the structural work possible, and Dimitri Chirgadze and colleagues (Biochemistry Department), Cambridge, who did the imaging by electron microscopy,” says Professor Kunji.

The findings appeared on 18 April in Science Advances, with the work supported by the Medical Research Council. The work was done in collaboration with the National Institute of Neurological Disorders and Stroke (NIH-NIDS) in the United States, as well as the Vrije Universiteit Brussel in Belgium.

Follow updates from the research group on BlueSky at @MRC-MBU.bsky.social and @mitocarriers.bsky.social.

MRC Mitochondrial Biology Unit

About Professor Edmund Kunji

Professor Kunji is Staff Fellow and Director of Studies in Natural Sciences (Biological) at Trinity Hall and Research Group Leader at the Medical Research Council (MRC) Mitochondrial Biology Unit. He researches the role of mitochondrial carrier proteins in the transport of metabolites, cofactors and ions across the mitochondrial inner membrane.