A team of researchers at Johannes Gutenberg University Mainz (JGU) has discovered a mechanism that causes mitochondrial dysfunction in Alzheimer’s patients, leading to a reduction in the supply of energy to the brain. This RNA modification, not previously reported, was identified by Professor Kristina Friedland and Professor Mark Helm. The study, published in Molecular Psychiatry, sheds light on the pathophysiology of Alzheimer’s disease and involved multiple institutions in its research.
Mitochondria, known as the powerhouse of the cell, play a crucial role in supplying energy to the brain through glucose metabolism. Dysfunction in mitochondria, induced by aging and amyloid-beta build-up, is a common occurrence in the early stages of Alzheimer’s disease. The respiratory chain in the inner mitochondrial membrane produces adenosine triphosphate (ATP) through the involvement of numerous proteins, including ND5, a subunit essential for complex I. Mutations in the mitochondrial encoded gene of ND5 can lead to severe mitochondrial disorders like Leigh syndrome.
The mRNA responsible for ND5 synthesis can undergo methylation, disrupting the translation process and resulting in fewer proteins being produced. The enzyme TRMT10C was identified by Friedland and Helm’s team as the cause of this methylation, leading to the suppression of ND5 protein biosynthesis. This suppression was observed in a cell model and the brains of Alzheimer’s patients, suggesting a connection between TRMT10C-induced methylation and mitochondrial dysfunction in Alzheimer’s disease.
In their study published in Molecular Psychiatry, the researchers concluded that TRMT10C-induced m1A methylation of ND5 mRNA contributes to mitochondrial dysfunction, potentially being involved in Aβ-induced mitochondrial dysfunction in Alzheimer’s disease. This newly identified mechanism provides valuable insights into the complex pathophysiology of Alzheimer’s disease and may open up new avenues for future research and therapeutic approaches. The research was supported by funding from the Collaborative Research Center / Transregio 319 “RMaP: RNA Modification and Processing.”
The discovery of this mechanism represents a significant advancement in understanding the underlying causes of mitochondrial dysfunction in Alzheimer’s disease, offering potential new targets for therapeutic interventions aimed at restoring normal energy supply to the brain. By identifying the enzyme TRMT10C as a key player in inducing methylation of ND5 mRNA, the researchers have highlighted a crucial pathway that may be targeted in future research efforts to develop novel treatments for Alzheimer’s disease. Additionally, the involvement of multiple institutions in this study underscores the collaborative nature of scientific research and the importance of interdisciplinary approaches in making breakthrough discoveries.
