40 Years of Studying RNA Import into Mitochondria: From Basic Mechanisms to Gene Therapy Strategies

Abstract

Mitochondria of many living species internalize nuclear DNA-encoded ribonucleic acids. The pools of imported RNA molecules, as well as fine mechanisms of these processes, are highly species-specific. To date, baker's yeast Saccharomyces cerevisiae are the best studied in this regard. Moreover, the processes of yeast RNA mitochondrial import have been the basis of modeling several gene therapy strategies aimed to palliate negative effects of pathogenic mutations in human mitochondrial DNA. In this review, we summarize our current knowledge about the molecular events taking place in course of yeast RNA import into mitochondria. Also, we describe how this process can be used for compensation of pathogenic mutations in mitochondrial genomes of humans. Key words mitochondria, non-coding RNAs, RNA import, targeting, mitochondrial translation, mitochondrial diseases, gene therapy, yeast, human MOLECULAR MECHANISMS OF RNA IMPORT INTO MITOCHONDRIA IN YEAST MODEL Since their discovery in XIX century, mitochondria were constantly raising the attention of researchers. Nowadays, an endosymbiotic theory of mitochondria origin is generally accepted (for review, see [1]). This theory says that a far ancestor of mitochondria was a free-living bacteria related to modern Rickettsia. In course of evolution, mitochondrial genes migrated to nucleus by currently unknown mechanism. However, modern mitochondria

Personalized Medicine in Mitochondrial Health and Disease: Molecular Basis of Therapeutic Approaches Based on Nutritional Supplements and Their Analogs

“…Something similar was already successfully tested by intranasal administration of growth factors for treating other brain injuries [ 210 , 211 , 212 ]. In addition, new pieces of evidence report important advancements in the delivery of oligonucleotides and nucleic acids in general in several biological models [ 213 , 214 ], by using liposomes and/or specific peptides for mitochondrial delivery [ 215 , 216 , 217 , 218 , 219 ], coherently with the recent mRNA-based vaccine success [ 220 , 221 ] and advances in the analysis of mitochondrial tRNA import [ 222 , 223 , 224 , 225 ].…”

Rational Designs at the Forefront of Mitochondria-Targeted Gene Delivery: Recent Progress and Future Perspectives

“…Additionally, the administration of RP/KALA-MITO-Porter did not alter the biomarker levels in mouse serum, suggesting its good biocompatibility for in vivo applications. However, as mammalian mitochondria, in which mitochondrial tRNA (tRNA) is supplied by mtDNA, do not import RNA molecules from the cytoplasm, unlike yeast and plant mitochondria, some researchers have questioned the mechanism by which mammalian mitochondria accomplish this cellular process. − Some studies have claimed that RNA is internalized into mammalian mitochondria from the cytoplasm. − Thus, further investigation into the mechanism by which nucleic acids enter mammalian mitochondria is necessary.…”

Evidence of mitochondria origin of SARS-CoV-2 double-membrane vesicles: a review.

“…Alternatively, the mitochondria could itself start viral protein synthesis with ribosomes located at the MOM 83 , and/or uptake vRNA from the cytoplasm after virus entry and vRNA release into the cytoplasm, although the former would require mitochondria localization sequences in those translocated molecules. In this regard, it is known that mitochondria are capable to import RNA from the cytoplasm through a pathway that involves the TOM/TIMM complex 84 , and SARS-CoV-2 RNA is predicted to locate at this organelle 71 . Indeed, this has been confirmed in a recent work published during the review of this manuscript that demonstrated that TOM20 mediates vRNA entry into mitochondria and that it is not colocalized with ER and lysosomal markers 33 .…”