Advanced Sequencing Technology Provides New Insights Into Human Mitochondrial Diseases
Researchers have for the first time been able
to investigate the abundance and methyl modifications of all
mitochondrial tRNAs in patients suffering from one of the most common
inherited mitochondrial tRNA mutations. The analysis pipeline revealed
quantitative changes that had dramatic effects on protein synthesis
within mitochondria.
The ability to
translate the genetic code into proteins is an essential step in all
living organisms. A cornerstone of this molecular process is the ability
of transfer RNA (tRNA) molecules to couple recognition of the genetic
code with the cognate amino acid, which are the building blocks of
proteins. Chemical modification of individual tRNAs is a critical step
for the decoding process during protein synthesis.
Mitochondria are known as the powerhouse of the cell and an essential
organelle that have a unique maternally-inherited genome and protein
synthesis machinery devoted to aerobic energy production. Mutations in
the tRNA genes encoded in the mitochondrial genome are the most frequent
cause of human mitochondrial disorders.
Despite the fact that all mitochondrial DNA mutations disrupt energy
production within the cell, specific mutations have distinct clinical
symptoms. The molecular basis by which these disorders develop into
diseases remains poorly understood.
One major deficit has been the lack of understanding of how primary
genetic mutations in the mitochondrial genome affect all of the tRNAs
and their respective chemical modifications. Past investigations into
this topic have been hampered by technological limitations and the
requirement for large amounts of patient material.
University of Helsinki researchers led by post-doctoral fellow Uwe Richter in the laboratory of Dr. Brendan Battersby at the Institute of Biotechnology, in collaboration with Tao Pan from the University of Chicago,
overcame these limitations using the latest advances in methodological
development of next-generation RNA sequencing to investigate the entire
pool of mitochondrial tRNAs at single nucleotide resolution. The results
of the study were published in the journal Nature Communications.
The approach allowed researchers for the first time to investigate
the abundance and methyl modifications of all mitochondrial tRNAs in
patients suffering from one of the most common inherited mitochondrial
tRNA mutations, MERRF, or myoclonic epilepsy with ragged red fibers.
The analysis pipeline revealed quantitative changes in tRNA abundance
and methyl modifications that had dramatic effects on protein synthesis
within mitochondria. By restoring the modification, the group was able
to delineate specific roles for the synthesis and also the stability of
mitochondrial proteins. Collectively, the report sheds new light on the
molecular mechanism in the development of human mitochondrial disorders.
Original publication:"RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis, Richter et al.," Nature Communications
Battersby Lab: Research projects and contact
Brendan Battersby
Research Director and Principal Investigator
https://www.helsinki.fi/en/news/life-science-news/advanced-sequencing-technology-provides-new-insights-into-human-mitochondrial-diseases
