Abstract
A prominent phenotype triggered by the loss of mitochondrial homeostasis is cellular senescence, characterized by cessation of growth and a senescence-associated secretory phenotype (SASP). We identified the G-rich RNA sequence-binding factor 1 (GRSF1) as a major mitochondrial protein implicated in this response. GRSF1 levels declined in senescent cells through reduced protein stability, and lowering GRSF1 abundance caused mitochondrial stress leading to elevated production of superoxide, increased DNA damage foci, and diminished cell proliferation. In addition, reducing GRSF1 increased the activity of a senescence-associated β-galactosidase (SA-β-gal) and the production and secretion of the SASP factor interleukin 6 (IL6). Together, our findings indicate that the decline in GRSF1 levels during cellular senescence contributes to impairing mitochondrial function, elevating ROS and DNA damage, suppressing growth, and implementing a pro-inflammatory program.
Highlights
Mitochondria are eukaryotic organelles essential for generating energy
The computational merging of proteins less abundant in the membrane fraction of senescent cells (Dn_Sen) [9], mitochondria-resident proteins [10], and RNA-binding proteins (RBPs) [11] revealed that G-rich sequence-binding factor 1 (GRSF1) and tRNA methyltransferase 1 (TRMT1) were the only mitochondria-residing RNAbinding protein (RBP) reduced in senescent fibroblasts (Fig. 1A)
The levels of GRSF1 were assayed in whole-cell lysates (WCL), membrane preparations (MP), and cytosolic preparations (CP) obtained from P and S WI-38 cells by Western blot analysis (Fig. 1B)
Summary
Mitochondria are eukaryotic organelles essential for generating energy. Mitochondrial homeostasis is controlled through gene expression programs governed by mitochondrial (mt)DNA and nuclear DNA. The RNAbinding protein (RBP) G-rich sequence-binding factor 1 (GRSF1) is encoded by nuclear DNA, translated in the cytosol, and directed to mitochondria through a mitochondria-localization signal [1]. GRSF1 is a constituent of mitochondrial RNA granules, large ribonucleoprotein (RNP) structures wherein RNase P processes precursor polycistronic mitochondrial RNAs to release mRNAs and tRNAs [1]. GRSF1 was found to associate with the nuclear DNA-encoded long noncoding (lnc)RNA RMRP in the mitochondrial matrix, thereby enhancing mitochondrial structure and function [3]. These studies provided evidence that GRSF1 RNPs critically maintain mitochondrial function
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