Aging: What underlies the mitochondrial stress response

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Tracing the activation mechanism of mitochondrial stress response and longevity

Tracing the activation mechanism of mitochondrial stress response and longevity in C. elegans. Credit: Terytty Yang Li and Arwen W. Gao, EPFL

Scientists at EPFL have discovered certain enzymes that play a central role in the stress responses that defend mitochondria from stress, and promote health and longevity.

Probably the most well-known organelle of the cell, mitochondria play a critical role in producing energy from food. So, it’s no surprise that mitochondria can get stressed and damaged. When stressed, mitochondria turn on multiple defense mechanisms: biochemical "domino" pathways that help them repair their defects and recover or improve their health.

Stressed mitochondria are particularly linked to aging and many age-related diseases. Problematic mitochondria are the cause of diseases in metabolism, the cardiovascular and neuromuscular systems, and even certain cancers. Because of how central mitochondria are to survival and health, they have evolved multiple stress response pathways to adapt their function to the ever-changing environment of the cell. But how these stress responses are regulated is still largely unknown.

Now, a team of scientists led by Johan Auwerx at EPFL’s School of Life Sciences has discovered that mitochondrial stress induces global but also very specific epigenetic changes, which involve enzymes that unravel compacted DNA in the cell’s nucleus to activate genes. These enzymes are called histone acetyltransferases because they interact with the histone proteins that pack DNA into a structure called chromatin.

Looking at the chromatin of the nematode C. elegans - a highly popular organism for studying aging - the scientists found that a histone acetyltransferase named CBP-1 is essential for the epigenetic changes caused by stress response of mitochondria, translating their stress signal into a coordinated transcription of a number of genes that are known to be involved in mitochondrial stress response.

"The beneficial effects of the mitochondrial stress response, such as resistance to pathogen infections, improved proteostasis against amyloid-- aggregation - one of the culprits of Alzheimer’s - and extending lifespan are almost completely dependent on these epigenetic changes," says Terytty Yang Li, the first author of the study. "Moreover, analysis in mouse and human populations, as well as genetic and pharmacological loss-of-function studies in mammalian cells, strongly suggest that this epigenetic mechanism involved in the regulation of the stress response, health and lifespan is also conserved in the mouse and human."

"Our work identifies an evolutionarily conserved node for mitochondrial stress signaling that defends mitochondrial function, and promotes health and longevity," says Johan Auwerx. "We are convinced that drugs that target these mitochondrial stress pathways may be interesting to curb the aging process".

Image: Tracing the activation mechanism of mitochondrial stress response and longevity in C. elegans. Activation of mitochondrial stress response by knocking down cco-1 (cytochrome c oxidase-1) in hsp-6p::gfp reporter C. elegans (left worm) defends mitochondrial function, promotes health and longevity. Li et al. show that silencing of cbp-1, which encodes the worm ortholog of mammalian acetyltransferases CBP/p300, remarkably blocks the mitochondrial stress response (right worm), highlighting a central role of CBP/p300 in mitochondrial homeostasis and longevity. Credit: Terytty Yang Li and Arwen W. Gao, EPFL