Mini-brain models advance understanding of mitochondrial disease mechanisms

Research team at the University of Bergen develops brain organoids to study mitochondrial dysfunction, offering new insights into neurological conditions including severe epilepsy and neurodegenerative diseases.

Scientists have achieved a significant advance in understanding mitochondrial diseases through the development of so­phisticated brain organoid models that replicate key aspects of cellular energy dysfunction. The research, published in Advanced Science on 6 March 2024, dem­onstrates how these ‘mini-brains’ can ef­fectively model the complex pathological features associated with mitochondrial disorders.

Understanding cellular powerhouse failure
The study, conducted at the University of Bergen’s Department of Clinical Medi­cine, focuses on the critical role of mito­chondria in neurological function. These cellular organelles, essential for energy production, are particularly crucial in brain tissue, where energy demands are exceptionally high. When mitochondrial function is compromised, it can lead to severe neurological manifestations, in­cluding epilepsy and potentially contrib­ute to neurodegenerative conditions.

Modelling disease progression
The research team, led by Group Leader Kristina Xiao Liang, has successfully de­veloped brain organoids that accurately mirror the cellular and molecular con­sequences of mitochondrial dysfunction. “The mini-brains give us a unique oppor­tunity to understand disease mechanisms at the cellular level and test potential treatments. This is a significant step to­wards developing new therapies for dis­eases like severe epilepsy,” explains Liang.

Applications in neurodegenerative research
Beyond their immediate application in studying mitochondrial diseases, these or­ganoid models show promise for investi­gating other neurological conditions. The research suggests potential applications in studying Alzheimer’s and Parkinson’s disease, where mitochondrial dysfunction has been implicated in disease progres­sion.

“These diseases often involve mito­chondrial dysfunction that can be studied in the mini-brains. They allow research­ers to study disease progression in real time, test personalized therapies, and identify new drug targets,” Liang notes.

Therapeutic implications
The development of these sophisticated organoid models represents a significant advance in the field of neurological dis­ease research. The ability to observe dis­ease processes in a controlled environ­ment that closely mimics human brain tissue provides researchers with unprec­edented opportunities to:

The models enable real-time observa­tion of disease progression, facilitating the development and testing of targeted therapeutic interventions. They also pro­vide a platform for investigating person­alised treatment approaches, considering individual genetic variations in mito­chondrial function.

While the current research focuses primarily on understanding basic disease mechanisms, the implications for thera­peutic development are substantial. The ability to study cellular responses in a complex, three-dimensional model sys­tem offers new possibilities for drug de­velopment and testing.

The research demonstrates the po­tential of organoid technology in bridg­ing the gap between basic scientific un­derstanding and clinical applications. As these models continue to be refined, they may provide increasingly valuable insights into the mechanisms underlying various neurological conditions.

Reference:
Liang, K. X., et al. (2024). Hallmark Molecular and Pathological Features of POLG Disease are Recapitulated in Cerebral Organoids. Advanced Science. https://doi.org/10.1002/advs.202307136