April 08, 2022
Continuing our theme of highlighting lifespan in yeast, this week’s study by Liu et al. in eLife looks at a possible mechanism for age-related loss of mitochondrial quality. As loss of mitochondrial quality is linked to the rate of building new mitochondria, and as mitochondrial biogenesis depends on the import of new building blocks through the mitochondrial membranes, the abundance of transporters is an important determinant. The authors wondered whether cells were “smart” enough to coregulate the level of transporters with the level of new building blocks.
To get at this question, they overexpressed the translocases of the outer membrane (TOM) proteins to ask if the overabundance of a particular one caused the overabundance of representative mitochondrial proteins, i.e. displayed a regulatory role. Of these, only TOM70 overexpression (OE) increased the abundance of the four representative mitochondrial proteins. They further showed that TOM70 OE led to increased levels of mitochondrial DNA, likely via Mip1p, the mitochondrial DNA polymerase gamma. As further evidence of the role of TOM70 in regulation, the tom70∆ knockout led to the reverse effect from OE, i.e. reduction in levels of both mitochondrial proteins and mtDNA. Tom70p is a well-conserved receptor within the TOM complex, but this role in regulation of mitochondrial biogenesis is a novel finding.
The authors then examined a number of possible intermediate signaling possibilities between Tom70p and the increased abundance of their target proteins. By disrupting various transcription factors and assessing reactive oxygen species, they saw only partial blockage by loss of any one signaling partner, and thus concluded that Tom70p works via multiple pathways.
As TOM70 appears to have a role in regulating new mitochondria, and mitochondrial defects are well established as an indicator of age, the authors asked about connections between TOM70 and aging. They first noted that Tom70p levels go down over time across many organisms. Is this a cause or an association? To counteract the wild-type reductions in Tom70p levels, they overexpressed TOM70 and then examined age-related phenotypes. Higher levels of Tom70p reversed age-associated loss of mitochondrial membrane potential, age-related reductions in other mitochondrial proteins, and, indeed, extended the lifespan of yeast. Further, the tom70∆ knockout once more showed the reverse effects, leading to accelerated aging and reduced lifespan.
Using the remarkable power of yeast, the authors were then able to study the mechanics of the reduction in Tom70p over time. They found that mRNA levels reduce over time due to loss of transcriptional activity, which was rescuable by changes made to the TOM70 promoter. Further, they showed the degradation of Tom70p increased over time due to increased levels of the protein Dnm1p, involved in sorting proteins for degradation under age-related vacuole deacidification. Thus, TOM70 mRNA levels decrease and Tom70p protein becomes less stable, providing redundancy in reduction of a protein that activates mitochondrial biogenesis. With the relative ease possible in yeast, the authors made important headway in revealing these mechanistic links between mitochondrial quality and aging.
Categories: Research Spotlight