Fight Aging!

Researchers here implicate an age-related reduction in Tom70 levels in the decline in mitochondrial function that takes place in later life. Mitochondria are the power plants of the cell; when their production of the chemical energy store molecule ATP is diminished, then all cell functions suffer as a result. Mitochondrial dysfunction with age is thought to produce a significant contribution to degenerative aging, and a broad range of research and development efforts are devoted to finding ways to address this problem. Research into Tom70 is at a very early stage, so it remains to be seen as to how useful this discovery will be. It seems likely, at the present time, based on what is known now, that the most important approaches to mitochondrial aging will be (a) epigenetic reprogramming to restore youthful expression of relevant proteins and (b) replacement of a patient's mitochondria via intravenous delivery of large numbers of mitochondria manufactured in cell cultures, to be taken up by cells and put to work.

Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins.

Here, we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription, biogenesis, and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mitochondrial DNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan in budding yeast. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.

Link: https://doi.org/10.7554/eLife.75658