Inside every cell in your body, mitochondria are hard at work converting food into energy. These microscopic power plants are essential to life—but scientists have long struggled to understand exactly how they build their own protein-making machinery. Now, a team at Karolinska Institutet has captured the process in unprecedented detail, offering new hope for treating energy-linked diseases.
In a study published in Nature Communications, researchers used advanced cryo-electron microscopy to photograph the assembly of the mitochondrial small ribosomal subunit—the core of the mitoribosome, the cell's protein factory. What they discovered challenges an old assumption: the process is not a tidy, step-by-step assembly line, but a flexible, modular system where different regions develop simultaneously, like a orchestra tuning up before a performance.
"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," said Anas Khawaja, co-corresponding author at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.
The research pinpointed two proteins—PUS1 and mtIF2—as critical players in this assembly. PUS1 was already known for its role in modifying RNA, but the team revealed it also stabilizes a key region of ribosomal RNA that forms part of the decoding center, where the ribosome reads genetic instructions to build proteins. Mutations in PUS1 have been linked to MLASA, a rare mitochondrial disorder that impairs muscles and metabolism.
By mapping exactly how these proteins work together, the researchers have opened a window into how errors in ribosome assembly can cascade into disease—particularly in tissues with the highest energy demands: the brain, heart, and muscles.
"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 said.
For the millions of people living with mitochondrial diseases—many of which remain poorly understood and lack effective treatments—this research marks a meaningful step forward. By showing precisely where the assembly process can go wrong, scientists now have clearer paths to explore for potential interventions.