A team of researchers from Johannes Gutenberg University Mainz (JGU) has identified a mechanism that causes mitochondrial dysfunction in Alzheimer’s patients, resulting in a reduction in energy supply to the brain. “This effect is attributable to a modification of RNA that has not been previously reported,” said Professor Kristina Friedland from the Institute of Pharmaceutical and Biomedical Sciences at JGU. She supervised the related study in collaboration with her colleague Professor Mark Helm. Its results contribute to a better understanding of the pathophysiology of Alzheimer’s disease. Groups from the University Medical Center of Mainz, the Institute of Molecular Biology (IMB), the University of Lorraine and the Medical University of Vienna also participated in the research. The corresponding article has been published in Molecular psychiatry.
‘Cell power’ affected by functional disorder
Mitochondria, often called the powerhouse of the cell, are organelles within cells that are in charge of energy supply throughout the body and particularly in the brain. For 95 percent of its energy, the brain depends on glucose metabolism in the mitochondria. It has long been known that impaired glucose metabolism occurs in the early stages of Alzheimer’s disease. This deterioration is due to the poor functioning of the mitochondria induced by the aging process and the accumulation of beta amyloid.
An energy source in the form of adenosine triphosphate (ATP) is formed in the inner mitochondrial membrane through a sequence of reactions known as the respiratory chain. More than a thousand proteins are involved in this process and are transported from the cell nuclei to the mitochondria. “But there are also proteins that are synthesized by the mitochondria themselves. One of them is ND5, a subunit of complex I of the respiratory chain,” explained Professor Kristina Friedland. A substance called NADH gives electrons to complex I, which transfers them to ubiquinone, resulting in ubiquinol. During this process, four proteins are pumped from the matrix into the intermembrane space. ND5 plays an important role in this regard and any mutation of the mitochondrial gene encoded by this subunit can lead to severe mitochondrial disorders, such as Leigh syndrome.
It has already been shown that the mRNA that provides the instructions for the synthesis of this protein can undergo methylation. In the body’s cells, mRNA carries genetic information and, together with tRNA, is responsible for its translation into proteins. Methylation of mRNA causes a change in its chemical structure so that it can no longer interact properly with tRNA. “The synthesis process is impaired and fewer proteins of the ND5 subunit are formed, which is of central importance for complex I, because the entire process begins in the respiratory chain,” Friedland added.
The TRMT10C enzyme causes methylation and therefore inhibition of ND5 synthesis.
Friedland and Helm’s teams from the Institute of Pharmaceutical and Biomedical Sciences at the University of Mainz were able to show that it is an enzyme called TRMT10C that induces this methylation and, therefore, the subsequent repression of ND5. The researchers observed a suppression of protein biosynthesis of the ND5 subunit in a suitable cell model, as well as in the brains of Alzheimer’s patients.
As the authors state in their article in Molecular psychiatry: “As a consequence, here demonstrated for the first time, TRMT10C induced m1A methylation of ND5 mRNA leads to mitochondrial dysfunction. “Our findings suggest that this newly identified mechanism could be involved in Aβ-induced mitochondrial dysfunction.” The research was funded as part of the Collaborative Research Center/Transregio 319 “RMaP: RNA Modification and Processing.”