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May 10, 2011

Absence of Mitochondrial Translation Control Proteins Extends Life Span by Activating Sirtuin-Dependent Silencing

A SOV1 Deletion Extends Life Span without Affecting Steady-State Levels of ROS or Oxidative Damage

Mitochondria are the body's energy producers, the power stations inside our cells. Researchers at the University of Gothenburg, Sweden, have now identified a group of mitochondrial proteins, the absence of which allows other protein groups to stabilise the genome. This could delay the onset of age-related diseases and increase lifespan.

A research team has now identified a group of mitochondrial proteins that are involved in this type of aging regulation. The researchers found that a group of proteins called MTC proteins, which are normally needed for mitochondrial protein synthesis, also have other functions that influence genome stability and the cell's capacity to remove damaged and harmful proteins.

Molecular Cell journal - Absence of Mitochondrial Translation Control Proteins Extends Life Span by Activating Sirtuin-Dependent Silencing



Highlights
* Yeast mitochondrial translation control (MTC) proteins affects aging
* Absence of MTCs extends life span and enhances nuclear silencing
* MTCs affects life span through the sirtuin, Sir2p
* MTC deficiency boosts Msn2/4p-dependent homeostatic performance

Summary
Altered mitochondrial functionality can extend organism life span, but the underlying mechanisms are obscure. Here we report that inactivating SOV1, a member of the yeast mitochondrial translation control (MTC) module, causes a robust Sir2-dependent extension of replicative life span in the absence of respiration and without affecting oxidative damage. We found that SOV1 interacts genetically with the cAMP-PKA pathway and the chromatin remodeling apparatus. Consistently, Sov1p-deficient cells displayed reduced cAMP-PKA signaling and an elevated, Sir2p-dependent, genomic silencing. Both increased silencing and life span extension in sov1Δ cells require the PKA/Msn2/4p target Pnc1p, which scavenges nicotinamide, a Sir2p inhibitor. Inactivating other members of the MTC module also resulted in Sir2p-dependent life span extension. The data demonstrate that the nuclear silencing apparatus senses and responds to the absence of MTC proteins and that this response converges with a pathway for life span extension elicited by reducing TOR signaling.

Some theories of human aging suggest that the power generators of the cell, the mitochondria, play a part in the process. In addition to supplying us with energy in a usable form, mitochondria also produce harmful by-products -- reactive oxyradicals that attack and damage various cell components. Eventually these injuries become too much for the cell to cope with, and it loses its capacity to maintain important functions, so the organism starts to age. That's the theory anyway. Oddly enough, several studies have shown that certain mitochondrial dysfunctions can actually delay aging, at least in fungi, worms and flies. The underlying mechanisms have yet to be determined.

"When a certain MTC protein is lacking in the cell, e.g. because of a mutation in the corresponding gene, the other MTC proteins appear to adopt a new function. They then gain increased significance for the stabilisation of the genome and for combating protein damage, which leads to increased lifespan," says Thomas Nyström of the Department of Cell and Molecular Biology.

He adds, "These studies also show that this MTC-dependent regulation of the rate of aging uses the same signalling pathways that are activated in calorie restriction -- something that extends the lifespan of many different organisms, including yeasts, mice and primates. Some of the MTC proteins identified in this study can also be found in the human cell, raising the obvious question of whether they play a similar role in the regulation of our own aging processes. It is possible that modulating the activity of the MTC proteins could enable us to improve the capacity of the cell to delay the onset of age-related diseases. These include diseases related to instability of the genome, such as cancer, as well as those related to harmful proteins, such as Alzheimer's disease and Parkinson's disease. At the moment this is only speculation, and the precise mechanism underlying the role of the MTC proteins in the aging process is a fascinating question that remains to be answered."

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