Suppression of mitochondrial protein import as a new longevity mechanism

Mitochondrial function is strongly linked with longevity. Dysfunctional mitochondria tend to accumulate with age and correlate with multiple life-threatening maladies such as neurodegenerative disorders, cardiovascular disease, and cancer. Given the variety and severity of associated conditions, a long-standing goal is to preserve mitochondrial function through aging by enhancing mitochondrial biogenesis and quality control system.  

The mitochondrial protein import system largely defines mitochondrial biogenesis (the process, by which mitochondrial number increases) and function. Protein import regulates the pace of mitochondrial biogenesis. However, an increased rate that ensures a robust mitochondrial network leads to the accumulation of dysfunctional organelles, which may have detrimental effects and is often linked with age-related diseases.

The mitochondrial protein import system is evolutionarily conserved from yeast to humans and regulates the translocation of up to 99% of all mitochondrial proteins. Compromised protein import leads to the accumulation of proteins and disruption in signaling and cell homeostasis. Previously it was shown that reduced mitochondrial load protects against cellular senescence.

However, reducing the mitochondrial load had never been tested before as a possible longevity intervention. Lionaki et al., in their study, directly assessed how the reduced protein import influences physiology in C. elegans nematodes. They showed that inhibition of the protein import results in the activation of proteostatic (related to dynamic regulation of function of the entire set of proteins) mechanism – mitochondrial unfolded protein response (UPRmt). This mechanism is a cellular stress response that responds to the presence of misfolded or unfolded proteins and protects the normal functionality of a cell by halting protein translation, degrading misfolded proteins, and initiating further protein-degrading pathways. UPRmt then triggers a mitochondrial protein import suppression (MitoMISS) – a putative novel longevity pathway discovered by authors. In nematodes, initiation of MitoMISS resulted in slightly increased lifespans. From a metabolism point of view, the beneficial effects of triggering this mechanism are connected to a longevity-related catabolic reaction, similar to those appearing during fasting or caloric restriction.

Furthermore, it was previously shown that dietary supplementation of several amino acids (namely methionine, serine, glycine, histidine, arginine, and lysine) has also promoted longevity in nematodes. Lionaki et al. discovered that MitoMISS triggers an increase in intracellular levels of serine, glycine, and threonine due either to increased serine uptake or increased de novo serine biosynthesis. Notably, inhibition of de novo biosynthesis abolishes MitoMISS-associated longevity, which may serve as proof that the de novo branch is causatively linked to the longevity phenotype.

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