The link between protein synthesis and mitochondrial degradation: Towards a unified mechanism of aging

The fidelity of protein synthesis is necessary for a properly functioning organism. In an aged animal, the overall rates of protein synthesis and degradation/recycling decline with age. Not only does this decrease the number of structural and enzymatic proteins available, but it increases the half life of proteins, perhaps allowing more time for these proteins to become oxidatively damaged.

Protein synthesis is also linked to nutrient availability through the TOR signaling pathway, implicating protein synthesis in the mechanism of life extension by calorie restriction (CR). CR counteracts the decline in protein turnover seen with age. Inhibiting protein synthesis also increases lifespan in C. elegans.

Wang et al examined the link between the rate of protein synthesis and mitochondrial degeneration. Working in yeast, they introduced a mutation into adenine nucleotide translocase (aac2^A128P), a protein located on the mitochondrial membrane. This mutation mimics the human disease progressive external ophthalmoplegia (PEO). The authors speculate that aac2^A128P might upset the availability of nucleotides, which in turn could cause deletions of mtDNA, a hallmark of PEO. In addition, they show that the introduction of aac2^A128P causes a decrease in membrane potential, which has already been shown to play a key role in aged mitochondria. aac2^A128P mutants also have a decreased replicative lifespan.

The authors next tested whether any known lifespan-extending mutations can suppress the mitochondrial dysfunction induced by the aac2^A128P mutation. Three of these mutations were particularly robust in reversing the aac2^A128P mutation. sch9Δ, rpl6BΔ and rei1Δ on a aac2^A128P background were able to form viable colonies at almost wild type levels. SCH9 is involved in nutrient sensing; RPL6B is a protein that makes up the ribosome; and REI1 is involved in ribosome processing. Overexpression of the well-known yeast sirtuin SIR2 did not have any effect on replicative lifespan in the aac2^A128P mutant.

sch9Δ, rpl6BΔ and rei1Δ mutants, even with the aac2^A128P mutation, outlived their wild type counterparts. The lethal aac2^A128P/phb1Δ double mutant was still viable with these three life-extending mutations. phb1Δ mutants have reduced mitochondrial membrane potentials and are susceptible to ethidium bromide. sch9Δ, rpl6BΔ and rei1Δ mutants on a phb1Δ background were resistant to ethidium bromide. CR had similar effects as these three lifespan-extending mutants, but other long-lived mutants, like tor1Δ, were only able to suppress the aac2^A128P – and not the aac2^A128P/phb1Δ double mutant – defect in mitochondrial membrane potential.

Might mitochondrial membrane potential be linked to protein synthesis? The researchers found that all of the lifespan-extending mutations examined had reduced total protein synthesis. sch9Δ, rpl6BΔ and rei1Δ mutants had some of the largest decreases. According to the authors, lower rates of protein translation will reduce stress from unassembled protein complexes. “Reduction of cytosolic protein synthesis may lower the overall loading of proteins onto the mitochondrial inner membrane and promote mitochondrial membrane potential maintenance.”

To examine the link between mitochondrial membrane potential and protein synthesis, the authors looked at the yme1Δ mutant. YME1 encodes a protease important for protein turnover, so, according to the authors, the altered mitochondrial membrane potential of the aac2^A128P mutant will worsen with decreased protein turnover. sch9Δ, rpl6BΔ and rei1Δ mutants were able to suppress the lethal aac2^A128P/yme1Δ double mutant.

This paper links two aging-associated deficiencies: mitochondrial defects and decreases in protein synthesis. These connections are becoming more and more common in the aging field. But why did some life-extending mutations cause reversions in the aac2^A128P mutant while others didn’t? How many paths are there to extended longevity?

The data above presents another conundrum. Protein synthesis declines with age, yet decreasing protein synthesis extends lifespan. What’s going on here? My guess is that decreased protein synthesis when you’re young in addition to inhibiting the decline in protein translation as you get older will delay the aging process.

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