Research Paper Volume 18 pp 30—44
Aging-associated mitochondrial circular RNAs
- 1 Department of Oncology Science, University of Oklahoma, Oklahoma City, OK 73104, USA
- 2 Department of Pharmacy Practice and Pharmaceutical Science, College of Pharmacy, University of Minnesota, Duluth, MN 55812, USA
- 3 Department of Pathology, College of Korean Medicine, Sangji University, Wonju-si, Gangwon-do 26339, Republic of Korea
- 4 Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- 5 Department of Biochemistry, Chonnam National University Medical School, Hwasun 58128, Republic of Korea
- 6 Department of Pathology, University of Oklahoma, Oklahoma City, OK 73104, USA
Received: August 25, 2025 Accepted: January 6, 2026 Published: February 10, 2026
https://doi.org/10.18632/aging.206354How to Cite
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), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
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 mitochondrial chromosome, chrM, 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 fibroblast. 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.