Abstract
Arginyltransferase 1 (ATE1) is an evolutionary-conserved eukaryotic protein that localizes to the cytosol and nucleus. It is the only known enzyme in metazoans and fungi that catalyzes posttranslational arginylation. Lack of arginylation has been linked to an array of human disorders, including cancer, by altering the response to stress and the regulation of metabolism and apoptosis. Although mitochondria play relevant roles in these processes in health and disease, a causal relationship between ATE1 activity and mitochondrial biology has yet to be established. Here, we report a phylogenetic analysis that traces the roots of ATE1 to alpha-proteobacteria, the mitochondrion microbial ancestor. We then demonstrate that a small fraction of ATE1 localizes within mitochondria. Furthermore, the absence of ATE1 influences the levels, organization, and function of respiratory chain complexes in mouse cells. Specifically, ATE1-KO mouse embryonic fibroblasts have increased levels of respiratory supercomplexes I+III2+IVn. However, they have decreased mitochondrial respiration owing to severely lowered complex II levels, which leads to accumulation of succinate and downstream metabolic effects. Taken together, our findings establish a novel pathway for mitochondrial function regulation that might explain ATE1-dependent effects in various disease conditions, including cancer and aging, in which metabolic shifts are part of the pathogenic or deleterious underlying mechanism.
Highlights
Mitochondria are the eukaryotic organelles responsible for oxidative phosphorylation (OXPHOS)
To gain further insight into the relationship between Arginyltransferase 1 (ATE1) and mitochondria from the perspective of molecular evolution, we examined the status of mitochondrial development and the presence of the ATE1 gene in several branches of eukaryotes
Consistent with the observations in mammalian cells, we found that the deletion of ate1 in budding yeast lead to slower growth in respiratory media (Figure 3F), reduced endogenous cell respiration by nearly 30%, and attenuated the mitochondrial membrane potential by more than 50% (Figures 3G,H)
Summary
Mitochondria are the eukaryotic organelles responsible for oxidative phosphorylation (OXPHOS). They originated from an endosymbiotic event between a respiratory-competent alpha-proteobacteria and an ancient archaea host cell (Bock, 2017). Regulatory mechanisms coordinating mitochondrial catabolism have been adjusted to meet the energy and biomass requirements of the eukaryotic cell. Most of the original bacterial genes have been transferred to the nucleus of the host cell. The mitochondrial genome (mtDNA) only encodes for a handful of protein-coding genes (8 in yeast, 13 in mammals). The remaining mitochondrial proteome is encoded by the nuclear genome, synthesized in the cytoplasm, and imported into mitochondria. Mitochondrial functions are under nuclear control, which involves regulatory processes that are not fully understood
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