Mitochondria is a powerhouse of the cell. It plays a vital role in producing energy from food. Meanwhile, it can get stressed and damaged. Under stressful conditions, mitochondria activate their multiple defense mechanisms: biochemical “domino” pathways that help them repair their defects and recover or improve their health.
Stressed mitochondria are largely involved in aging, cancer, age-related neurodegenerative, and metabolic syndrome. In view of how central mitochondria are to survival and health, they have advanced numerous stress response pathways to adjust their function to the cell’s consistently changing climate. However, how these stress responses are controlled is still, to a great extent, obscure.
In the recent study researchers have discovered certain enzymes that play a significant role in stress responses that defend mitochondria from stress and promote health and longevity. They found that stressed mitochondria induce global and very specific epigenetic changes, which involve enzymes that unravel compacted DNA in the cell’s nucleus to activate genes. Known as histone acetyltransferases, these enzymes interact with the histone proteins that pack DNA into chromatin structure.
The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress
Organisms respond to mitochondrial stress by activating multiple defense pathways, including the mitochondrial unfolded protein response (UPRmt). However, how UPRmt regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here, we identify CREB-binding protein-1 (CBP-1), the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPRmt, as well as the mitochondrial stress-induced immune response, with involvement also in the reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans.
Mechanistically, CBP-1 acts downstream of the histone demethylases JMJD-1.2 and JMJD-3.1 and upstream of UPRmt transcription factors, including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts the UPRmt in mammalian cells, while forced expression of p300 is sufficient to activate it. These results highlight an evolutionarily conserved mechanism that determines the mitochondrial stress response and promotes health and longevity through CBP/p300.