Cellular metabolism is a complex web of connections. For any well known protein that regulates metabolism in ways relevant to aging that can be affected directly by various small molecules, gene therapies, or mutations, there are probably a score of other ways to indirectly affect its expression and activity. The mTOR pathway is well researched, as suppression of mTOR activity is a part of the response to low nutrient levels that adjusts cellular biochemistry in favor of conservation and increased maintenance, such as via an upregulation of autophagy. This tends to slow aging. Even though mTOR and its proximate biochemistry is a relatively well researched area of molecular biology, researchers continue to find new links to other aging-related areas of interest.
In today's open access paper, the authors draw a connection between mild suppression of mitochondrial activity and mTOR activity via a convoluted chain of interactions centered around an uncoupling protein. Mitochondria are the power plants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP) in an energetic process that produces damaging free radicals as a side-effect. A mild suppression of this mitochondrial activity (whether achieved via mutation, uncoupling, or other approaches) can slow aging in laboratory species, and the resulting changes include reduced mTOR activity. That in turn upregulates autophagy and helps to clear out damaged structures and protein aggregates that can harm cell function. A better understanding of how mitochondria instruct the rest of the cell to improve its function might lead to better ways to artificially induce this behavior.
Mitochondria are subcellular organelles that utilize an electron transport chain (ETC) to produce cellular energy and also synthesize numerous metabolites that efflux to the cytosol. Mild knockdown of mitochondrial ETC proteins prolongs lifespan, a phenomenon that has been observed in diverse organisms including C. elegans, Drosophila, and mice. In mammalian cells, ETC perturbation or mitochondrial distress represses the mechanistic target of rapamycin complex 1 (mTORC1) pathway through activation of the transcription factor ATF4. Studies in Drosophila muscle have found ETC perturbation to repress systemic insulin signaling through expression of ImpL2, an inhibitor of Drosophila insulin-like peptides (Dilps). Repression of either mTORC1 or insulin signaling is established to extend lifespan; however, the mechanisms underlying this mitochondrial-distress-mediated life extension are not yet completely understood.
Aspartate (asp), a proteogenic amino acid, is synthesized in the mitochondrial matrix from glutamate and oxaloacetic acid (OAA), a tricarboxylic acid (TCA) cycle metabolite. Of note, asp synthesis requires integral mitochondrial function. In mammalian cells, treatment with an ETC inhibitor depletes asp due to impairment of NADH flux, which is required for integrity of the TCA cycle. Perturbation of asp synthesis impairs cell proliferation, and in endothelial cells impairs the cytosolic mTORC1 pathway.
Here we show that in flies mutation in uncoupling protein 4a (Ucp4a), which encodes a mitochondrial aspartate transporter, can extend lifespan without restricting feeding. Remarkably, the life-extension effect of Ucp4a mutation is specifically due to knockdown of Ucp4a in muscles; knockdown in other tissues was not effective in life-extension. We find that protein aggregates, a characteristic of muscle aging, are reduced by Ucp4a knockdown in muscles. Consistently, Ucp4a mutants and lines with Ucp4a knockdown in muscle maintain healthier muscle than control flies, as suggested by observation of enhanced locomotor activity in aged flies.
Aspartate (Asp) is converted to asparagine (Asn) by the asparagine synthetase (ASNS) enzyme in the cytosol, suggesting that Ucp4a knockdown is likely to reduce cytosolic Asn. This reduction might be a signal that relates to inhibition of the mTORC1 pathway. This possibility is supported by a recent finding that inhibition of glutaminolysis, which is required for asp synthesis, activates the ATF4-mediated pathway to suppress mTORC1 activity through expression of the mTORC1 negative regulators Sestrin2 and Redd1. Ultimately, asp reduction-mediated lifespan extension might require inhibition of the mTORC1 pathway. Further confirmatory research remains required.
View the full article at FightAging
