In a groundbreaking study published in the latest volume of Aging-US, researchers have unveiled novel insights into mitochondrial circular RNAs (circRNAs) and their profound implications in human aging and cellular senescence. The investigation, led by Hyejin Mun at the University of Oklahoma and involving collaborators Je-Hyun Yoon and Young-Kook Kim, explores the dynamic profiles of circRNAs encoded by the mitochondrial genome, particularly within Peripheral Blood Mononuclear Cells (PBMCs), revealing significant age-associated alterations.
Central to the study is the discovery that a substantial portion of circRNA junctions derive from mitochondrial DNA, with a persistent emphasis on MT-RNR2—the mitochondrial 16S ribosomal RNA gene—which produces the most abundant mitochondrial circRNA. These circRNAs are covalently closed RNA molecules that result from a back-splicing event linking a downstream splice donor to an upstream splice acceptor, forming covalently closed loops distinct from linear RNAs. The investigators show a striking reduction of circMT-RNR2 in PBMCs from elderly cohorts and in senescent human diploid fibroblasts (WI-38 cells), illuminating a potential link between mitochondrial RNA circularization and aging phenotypes.
Leveraging high-throughput total RNA sequencing, the team mapped mitochondrial circRNA junctions by employing algorithms sensitive to non-canonical splicing events, enabling them to discern circular RNA junctions from linear transcripts. The abundance of circMT-RNR2 decreases sharply with increased donor age, suggesting that mitochondrial RNA circularization is compromised or altered during the aging process. Further, in WI-38 fibroblasts subjected to replicative senescence, a similar depletion of circMT-RNR2 was observed, pointing to a conserved mechanism in cellular aging.
Crucially, the study sheds light on the functional role of GRSF1, a mitochondrial RNA-binding protein traditionally recognized for its role in RNA processing and mitochondrial gene expression regulation. Not only does GRSF1 bind linear MT-RNR2 transcripts, but it also binds circular MT-RNR2 RNA species. Experimental knockdown of GRSF1 significantly diminished circMT-RNR2 levels, indicating that GRSF1 is integral to circRNA biogenesis or stability within mitochondria. This finding suggests that GRSF1 serves as a nexus between mitochondrial RNA metabolism and age-related decline in mitochondrial function.
The biological significance of these mitochondrial circRNAs is further underscored by their impact on mitochondrial metabolism. Loss of GRSF1 correlates with a pronounced decrease in tricarboxylic acid (TCA) cycle intermediates, specifically fumarate and succinate. This metabolic shift is consistent with deteriorated mitochondrial function, which is a hallmark of aging cells. The study thus postulates that circMT-RNR2 may modulate mitochondrial energetics by influencing or stabilizing elements of the TCA cycle machinery, possibly through direct or indirect interactions.
At the cellular phenotypic level, diminished circMT-RNR2 and GRSF1 expression precipitate accelerated senescence, evidenced by characteristic markers such as increased senescence-associated β-galactosidase activity and altered mitochondrial membrane potential. These changes underscore the functional connection between mitochondrial circRNAs, metabolic integrity, and the proliferative capacity of cells. Hence, mitochondrial circRNAs emerge as novel regulatory molecules influencing cellular aging trajectories.
The authors also trace the molecular architecture of circMT-RNR2 junctions by aligning their findings with prior studies identifying RNA back-splice junctions, suggesting that mitochondrial circRNAs might be generated via mechanisms analogous to nuclear genome-derived circular RNAs. However, the precise biogenesis pathways remain elusive, particularly in mitochondria traditionally viewed as lacking the complex splicing machinery found in the nucleus.
Future research directions outlined emphasize the necessity to elucidate the mitochondrial circular RNA biogenesis mechanism, including the potential involvement of trans-splicing or unique mitochondrial RNA-modifying enzymes. Clarifying whether circMT-RNR2 can interact directly with metabolic enzymes or participate in feedback loops modulating mitochondrial bioenergetics could reveal new layers of mitochondrial regulation.
Moreover, the research team proposes extending in vivo studies involving diverse human cohorts and model organisms to fully delineate the physiological roles of mitochondrial circRNAs across aging. Determining if these circRNAs can serve as biomarkers or therapeutic targets to modulate mitochondrial function and delay age-related decline holds immense translational promise.
In summary, the study revolutionizes the understanding of mitochondrial transcriptomics by pinpointing circular RNAs as critical players in the aging process, linking them to mitochondrial metabolism and cellular senescence. It bridges RNA biology, mitochondrial energetics, and gerontology, opening new avenues for leveraging mitochondrial circRNAs as modulators of aging and metabolic health.
The implications of these findings resonate beyond fundamental biology, suggesting that manipulation of mitochondrial circRNAs or their regulatory proteins like GRSF1 could offer novel strategies to ameliorate age-dependent mitochondrial dysfunctions, which underpin various age-associated diseases.
This pioneering work paves the way for a paradigm shift in mitochondrial biology, unveiling layered complexity in mitochondrial RNA species and their roles. Ultimately, mitochondrial circRNAs may emerge as key molecular nodes integrating genome regulation, metabolism, and aging.
Subject of Research: Not applicable
Article Title: Aging-associated mitochondrial circular RNAs
News Publication Date: 10-Feb-2026
Web References:
– Aging-US Volume 18 issue: https://www.aging-us.com/issue/v18i1/
– DOI link: http://dx.doi.org/10.18632/aging.206354
Image Credits: Copyright: © 2026 Mun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0).
Keywords: circular RNA, MT-RNR2, GRSF1, TCA cycle, aging
