A natural RNA surveillance mechanism is crucial to maintain the integrity of mitochondria’s encoded information for protein production and prevent the accumulation of potential disease-causing molecules.
The study, “Human mitochondrial degradosome prevents harmful mitochondrial R loops and mitochondrial genome instability,” was published in the journal Proceedings of the National Academy of Sciences (PNAS).
The DNA-encoded information is naturally translated into RNA coding sequences, which are then transformed into the functional proteins required for cells to properly function. During this tightly regulated process, it is common for some DNA-RNA hybrid molecules to be formed.
Named R-loops, these intermediate molecules are known to have important regulatory functions within the translation process. Still, if their balance is disrupted, they can become toxic, potentially contributing to genetic instability.
A team at Spain’s Andalusian Center for Molecular Biology and Regenerative Medicine has found that the degradasome (mtEXO) — a complex formed by SUV3 and PNPase enzymes whose function is to eliminate defective RNA produced in the mitochondria — is critical for maintaining mitochondrial DNA integrity.
Using experimental methods to genetically block SUV3 and PNPase enzymes, the team found that in the absence of functionally active mtEXO, mitochondria would accumulate RNA molecules. This result suggests that the degradasome complex is required for the correct degradation and turnover of mitochondrial RNA molecules.
Cells that lacked SUV3 and PNPase enzymes were found to accumulate DNA-RNA hybrid molecules, which were also found to be associated with significant changes in the structure of mitochondria.
Further analysis also revealed that loss of active mtEXO was linked to deficient mitochondrial DNA processing.
“Mitochondria are essential as the powerhouses of [animal] cells and there is growing evidence of their contribution to numerous human pathologies, such as neurodegenerative disorders and cancer,” researchers said. “The mitochondrial degradosome formed by SUV3 and PNPase plays an essential role in mitochondrial RNA turnover, contributing to mitochondrial [balance] and overall cellular function.”
The study’s findings provide new insights on the role of mtEXO “in preventing harmful R-loop accumulation in the mitochondrial genome as a way to warrant mtDNA integrity,” allowing the propagation of healthy mitochondria and preventing mitochondrial-related disorders.