RT Journal Article
SR Electronic
T1 DNA damage response signaling to mitochondria drives senescence
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.09.22.509001
DO 10.1101/2022.09.22.509001
A1 Shota Yamauchi
A1 Yuki Sugiura
A1 Junji Yamaguchi
A1 Xiangyu Zhou
A1 Takeru Odawara
A1 Shunsuke Fukaya
A1 Isao Naguro
A1 Yasuo Uchiyama
A1 Hidenori Ichijo
YR 2022
UL http://biorxiv.org/content/early/2022/09/22/2022.09.22.509001.abstract
AB Cellular senescence is a stress-induced irreversible cell cycle arrest typically accompanied by expression of the cyclin-dependent kinase inhibitor p16INK4a (hereafter referred to as p16) and mitochondrial dysfunction1. Recent studies have indicated that p16-expressing senescent cells accumulate in the body over time and contribute to aging1, 2. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA1. However, the molecular mechanisms linking DNA damage to senescence remain unclear. Here, we show that the outer mitochondrial transmembrane protein BNIP3 drives senescence by triggering a DNA damage response (DDR) of mitochondria. BNIP3 was identified in a genome-wide siRNA screen for genes required for p16 expression upon DNA damage. Mass spectrometric analysis of BNIP3-interacting proteins yielded the DDR kinase ATM and subunits of the mitochondrial contact site and cristae organizing system (MICOS) complex. BNIP3 is an ATM substrate that increases the number of mitochondrial cristae upon DNA damage. This increase enhances the oxidation of fatty acids to acetyl-CoA, an acetyl group donor, thereby promoting histone acetylation and associated p16 expression. Our findings indicate that DDR signaling to mitochondria promotes p16 expression by altering mitochondrial structure and metabolism and highlight the importance of nuclear–mitochondrial communication in senescence induction.Competing Interest StatementThe authors have declared no competing interest.