Some gene sequences can give rise to circular RNAs when transcribed. As a class, circular RNAs are not as well studied as other classes of molecule in the cell, but it is becoming apparent that, as for just about everything one might find in a cell, some circular RNAs become relevant in the context of aging. Here, researchers discuss findings relating to circular RNAs generated from mitochondrial genes. In particular circular RNAs for MT-RNR2 appear to meaningfully affect mitochondrial function, and lower levels of MT-RNR2 in older individuals may be involved in the age-related decline of mitochondrial function. The best way forward to a greater understanding is to manipulate MT-RNR2 expression and see what happens as a result. In general, improved mitochondrial function should be a good path to the production of therapies that improve health, but the question is always how great an improvement can be achieved, and that remains to be seen in this case.
During mammalian aging, there are changes in abundance of noncoding RNAs including microRNAs, long noncoding RNAs, and circular RNAs. Although global profiles of the human transcriptome and epitranscriptome during the aging process are available, the existence and function of mitochondrial circular RNAs originating from the mitochondrial genome are poorly studied. Here, we report profiles of circular RNAs annotated to the mitochondrial chromosome in young and old cohorts.
The most abundant circular RNA junctions are found in MT-RNR2, whose level is depleted in old cohorts and senescent fibroblasts. The mitochondria-localized RNA-binding protein GRSF1 binds various mitochondrial transcripts, including linear and circular MT-RNR2, with a distinct RNA motif. Linear and circular MT-RNR2 bind a subset of TCA cycle enzymes, suggesting their possible function in regulating glucose metabolism in mitochondria to preserve proliferating status in young cohorts. In human fibroblasts, depletion of GRSF1 reduced levels of circMT-RNR2 and fumarate/succinate, concomitantly accelerating cellular senescence and mitochondrial dysfunction.
Taken together, our findings demonstrate the existence and possible function of circular MT-RNR2 during human aging and senescence, implicating its role in promoting the TCA cycle. Future mechanistic studies will reveal how these mitochondrial circular RNAs are produced by trans-splicing, possibly, and how the circular RNAs accelerate the TCA cycle to preserve the proliferation status and suppress senescence as well as aging.
Link: https://doi.org/10.18632/aging.206354
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