Abstract
We have reported recently that the mitochondrial Na+/Ca2+ exchanger inhibitor CGP37157 extends lifespan in Caenorhabditis elegans by a mechanism involving mitochondria, the TOR pathway and the insulin/IGF1 pathway. Here we show that CGP37157 significantly improved the evolution with age of the sarcomeric regular structure, delaying development of sarcopenia in C. elegans body wall muscle and increasing the average and maximum speed of the worms. Similarly, CGP37157 favored the maintenance of a regular mitochondrial structure during aging. We have also investigated further the mechanism of the effect of CGP37157 by studying its effect in mutants of aak-1;aak-2/AMP-activated kinase, sir-2.1/sirtuin, rsks-1/S6 kinase and daf-16/FOXO. We found that this compound was still effective increasing lifespan in all these mutants, indicating that these pathways are not involved in the effect. We have then monitored pharynx cytosolic and mitochondrial Ca2+ signalling and our results suggest that CGP37157 is probably inhibiting not only the mitochondrial Na+/Ca2+ exchanger, but also Ca2+ entry through the plasma membrane. Finally, a transcriptomic study detected that CGP37157 induced changes in lipid metabolism enzymes and a four-fold increase in the expression of ncx-6, one of the C. elegans mitochondrial Na+/Ca2+ exchangers. In summary, CGP37157 increases both lifespan and healthspan by a mechanism involving changes in cytosolic and mitochondrial Ca2+ homeostasis. Thus, Ca2+ signalling could be a promising target to act on aging.
Highlights
Mitochondria, the organelle responsible of aerobic energy production, plays multiple roles in cellular Ca2+ homeostasis (Pizzo et al, 2012; Gherardi et al, 2020)
We have reported recently that CGP37157 extends lifespan on C. elegans worms with a bell-shaped concentration–response, so that the effect was obtained at submaximal concentrations, with higher doses producing no effect (García-Casas et al, 2019)
Our analysis reveals that CGP37157 acts downstream of daf-16/FOXO in the insulin pathway, involves TORC1 inhibition and functional mitochondria, induces changes in plasma membrane and mitochondrial Ca2+ fluxes, changes the expression of many lipid metabolism enzymes and increases the expression of the mitochondrial Na+/Ca2+ exchanger (mNCX) C. elegans homolog ncx-6 gene
Summary
Mitochondria, the organelle responsible of aerobic energy production, plays multiple roles in cellular Ca2+ homeostasis (Pizzo et al, 2012; Gherardi et al, 2020). Increase in mitochondrial [Ca2+] activates mitochondrial metabolism, linking cell activation to energy production. The rapid mitochondrial Ca2+-accumulation that occurs during cell stimulation constitutes a mechanism of transient buffering of cytosolic Ca2+ (Montero et al, 2000). CGP37157 Increases C. elegans Healthspan regulates a variety of phenomena triggered by cytosolic Ca2+, such as neurotransmitter secretion or muscle contraction. Mitochondria play an important role in the regulation of cell death induced by mitochondrial Ca2+ overload. The best known pathway for Ca2+ entry into the mitochondria is the mitochondrial Ca2+ uniporter (MCU), a Ca2+-activated Ca2+ channel present in the inner mitochondrial membrane (Gherardi et al, 2020), additional pathways must be present to explain the persistence of mitochondrial Ca2+
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