Senescent human astrocytes impair neuronal mitochondrial function through released factors

In cultured primary human astrocytes and human postmitotic neurons, researchers investigated how astrocyte senescence influences neuronal mitochondrial health. The team induced senescence in human astrocytes using doxorubicin. These senescent astrocytes accumulated smaller, ultrastructurally damaged mitochondria alongside elevated fission, fusion, and biogenesis markers. Despite this expansion, the senescent astrocytes exhibited lower mitochondrial membrane potential, reduced ATP, and decreased cellular metabolic activity. Senescence also altered the extracellular space. Conditioned medium from senescent astrocytes carried fewer mitochondrial particles with lower membrane potential and less ATP. When exposed to this medium, human postmitotic neurons experienced hydrogen peroxide accumulation, ATP depletion, and reduced metabolic activity without overt cell death. In contrast, medium from control astrocytes boosted neuronal levels of TOMM20 and PGC-1alpha.