Zakarian, A. | bioRxiv Science

bioRxiv2024

Calcium (Ca2+) fluxes at Mitochondria-ER Contact Sites (MERCS) are a new target of senolysis in Therapy-Induced Senescence (TIS).

O_LIThis study investigates the state of calcium (Ca2+) flux and Mitochondria-ER contact sites (MERCS) on Therapy-Induced Senescence (TIS). C_LIO_LITIS cells-induced by Doxorubicin and Etoposide increase their MERCS contact surface but exhibit a decreased ER-mitochondria Ca2+ flux. C_LIO_LITIS cells show decreased levels of IP3R isoforms and a decreased interaction between type 1 IP3R isoform and VDAC1. C_LIO_LIThe ER-mitochondria Ca2+ flux is essential to maintain the viability of senescence cells. C_LIO_LIInhibition of ER-mitochondria Ca2+ flux rise as a new target of senolysis in vitro and in vivo. C_LI

cell biology↗

bioRxiv2021

A feed-forward Ca2+-dependent mechanism boosting glycolysis and OXPHOS by activating Aralar-malate-aspartate shuttle, upon neuronal stimulation

Calcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In cortical neurons using glucose as only fuel, activation by NMDA, which elicits a strong workload dependent on Na+ entry, stimulates glucose uptake, glycolysis, pyruvate and lactate production, and OXPHOS in a Ca2+-dependent way. We find that Ca2+-upregulation of glycolysis, pyruvate levels and respiration, but not glucose uptake, all depend on Aralar/AGC1/Slc25a12, the Ca2+regulated mitochondrial aspartate-glutamate carrier, component of the malate-aspartate shuttle (MAS). Ca2+-activation of MAS increases pyruvate production, which directly fuels workload-stimulated respiration. Also it stimulates glycolysis. MCU silencing had no effect indicating that none of these processes required mitochondrial Ca2+. The neuronal respiratory response to carbachol was also dependent on Aralar, but not on MCU. We also find that cortical neurons are endowed with a constitutive ER-to-mitochondria Ca2+ flow maintaining basal cell bioenergetics in which Ryanodine receptors, RyR2, rather than InsP3R, are responsible for Ca2+ release, and in which MCU does not participate. The results reveal that in neurons using glucose MCU does not participate in OXPHOS regulation under basal or stimulated conditions, while Aralar-MAS appears as the major Ca2+-dependent pathway tuning simultaneously glycolysis and OXPHOS to neuronal activation.

neuroscience↗