HMN 2026: How mitochondria build their protein factories could help explain energy?linked disease

In a study published in Nature Communications, researchers at Karolinska Institutet have mapped key steps in the assembly of the mitochondrial ribosome, offering new clues to how defects in this process can lead to disease.

Mitochondria are known as the cell’s powerhouses, converting nutrients into energy. To do this, they rely on their own protein-producing machinery, the mitoribosome. A new study now shows how the small subunit of this machinery is assembled inside human cells, revealing previously unknown steps and factors involved in the process.

Using advanced cryo-electron microscopy, the researchers captured a series of structural snapshots that illustrate how different parts of the mitochondrial small ribosomal subunit mature. The findings suggest that assembly is not a simple step-by-step sequence, but a flexible and coordinated process in which different regions develop in parallel.

“We wanted to understand how the final stages of mitochondrial small ribosomal subunit assembly are controlled. What we found is that the process is not a simple linear pathway, but a modular and dynamic maturation process involving several factors acting at specific structural checkpoints,” says Anas Khawaja, co-corresponding author at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.

May offer targets for future therapies

The work highlights how errors in building the mitoribosome can impair energy production, particularly in tissues with high energy demands such as the brain, heart and muscles.

The study identifies two proteins, PUS1 and mtIF2, as important contributors to mitoribosome assembly. PUS1 was previously known mainly for its role in RNA modification, but the researchers now show that it also helps stabilize a key region of ribosomal RNA. This region forms part of the decoding center, where genetic information is read during protein synthesis.

Mutations in PUS1 have been linked to MLASA, a rare mitochondrial disorder that affects muscles and metabolism. By clarifying how PUS1 functions in ribosome assembly, the new findings may help explain how such mutations disrupt cellular energy production.

“Our structures provide a more detailed model for how mitochondrial ribosomes are formed and become functional, and understanding these mechanisms is important, as mitochondrial protein synthesis is central to energy metabolism and may offer targets for future therapies,” Khawaja says.

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