the stress response in the ER, mitochondrial stress is characterized by a mitochondrial unfolded protein response (UPR mt ) and initiation of a retrograde stress signaling pathway accompanied by impaired mitochondrial function and membrane potential
Ting Xiao, Xiuci Liang, Hailan Liu, Feng Zhang, Wen Meng and Fang Hu
Hyon-Seung Yi, Joon Young Chang and Minho Shong
chaperones and proteases as markers of UPR mt induction in vitro and in vivo ( Aldridge et al . 2007 , Haynes et al . 2010 , Fiorese et al . 2016 ). Recent studies demonstrated that the ATF4 pathway is activated in mammals upon mitochondrial stress
Ulas Ozkurede, Rishabh Kala, Cameron Johnson, Ziqian Shen, Richard A Miller and Gonzalo G Garcia
It has been hypothesized that transcriptional changes associated with lower mTORC1 activity in mice with reduced levels of growth hormone and insulin-like growth factor 1 are responsible for the longer healthy lifespan of these mutant mice. Cell lines and tissues from these mice show alterations in the levels of many proteins that cannot be explained by corresponding changes in mRNAs. Such post-transcriptional modulation may be the result of preferential mRNA translation by the cap-independent translation of mRNA bearing the N6-methyl-adenosine (m6A) modification. The long-lived endocrine mutants – Snell dwarf, growth hormone receptor deletion and pregnancy-associated plasma protein-A knockout – all show increases in the N6-adenosine-methyltransferases (METTL3/14) that catalyze 6-methylation of adenosine (m6A) in the 5′ UTR region of select mRNAs. In addition, these mice have elevated levels of YTH domain-containing protein 1 (YTHDF1), which recognizes m6A and promotes translation by a cap-independent mechanism. Consistently, multiple proteins that can be translated by the cap-independent mechanism are found to increase in these mice, including DNA repair and mitochondrial stress response proteins, without changes in corresponding mRNA levels. Lastly, a drug that augments cap-independent translation by inhibition of cap-dependent pathways (4EGI-1) was found to elevate levels of the same set of proteins and able to render cells resistant to several forms of in vitro stress. Augmented translation by cap-independent pathways facilitated by m6A modifications may contribute to the stress resistance and increased healthy longevity of mice with diminished GH and IGF-1 signals.