Pathway of mitochondrial disorder revealed

Yale scientists have discovered a molecular pathway that is implicated in maternally inherited deafness, a discovery that was published in Cell. Not only has this study shed light to the molecular interactions in the pathway, but it also has provided a solution for elucidating tissue specificity of human mitochondrial-based disorders.
The mitochondrion is a vital organelle that is considered to be the powerhouse of all of our cells. Through a certain process known as oxidative phosphorylation, mitochondria produce units of energy for our cells to carry out certain cellular activities. Mitochondria have their own DNA, which is maternally inherited and can be subject to mutations that lead to mitochondrial dysfunctions. These dysfunctions are implicated in diabetes, heart disease, cancer, neural degeneration and aging.
A milestone in determining the cause of maternally inherited deafness occurred back in 1993, when the A1555G mutation was discovered in human mtDNA (mitochondrial DNA). A1555G denotes a point mutation where an adenine nucleotide is mutated into a guanine in the 1555th nucleotide.
More specifically, A1555G is a mutation in the 12S rRNA gene that codes for a certain subunit of ribosomes in mitochondria. This gene was found to cause irreversible deafness, which implies that the crucial, irreplaceable cells within the inner ear were subject to an apoptotic pathway, or cell-death, due to this mutation.
A major obstacle in understanding mitochondrial diseases is the elucidation of its tissue specificity. Despite all cells in the body carrying the same mitochondrial mutation, the primary effect of the A1555G mutation is the eventual loss in hearing, in both mice and humans. This suggests that there is a cell-type specific response to the stress caused by the mutation.
The A1555G mutation impairs the ribosome, an organelle known for translation, the process in which cellular proteins are built. This can, downstream, cause defects in the process of oxidative phosphorylation, which is important for producing energy for cells.
However, it was found that the 12S rRNA was hypermethylated, due a consequent overexpression of mtTFB1, an enzyme that is implicated in methylation. Hypermethylation means that methyl groups were added to the 12S rRNA. The hypermethylation was key to the molecular defects instigating apoptosis.
Yale scientists hypothesized that the hypermethylation of 12S rRNA causes a stress signaling pathway that eventually leads to apoptotic susceptibility of cells. A pro-apoptotic transcription factor, E2F1, was identified to be one of the downstream contributors to cell death. Transcription factors, as E2F1, facilitate the expression of other proteins, which in this case are implicated in cell death.
This E2F1 pathway may have become a paradigm for other scientists to not focus on the immediate effects of defects in oxidative phosphorylation, but to find a possible link between apoptosis and retrograde signals caused by hypermethylation in mitochondrial ribosomes.