Succinate reduces biological activity and mitochondrial function of human adipose-derived stem cells.

Abstract

Elevated succinate accumulation has been demonstrated to be associated with metabolic and inflammatory disorders. Our previous study revealed that adipose-derived stem cells (ADSC) from obese individuals exhibit high succinate, reduced biological activity, and mitochondrial dysfunction. However, the precise role of succinate in these processes remains unclear. Here, we investigated the effects of excess succinate on cellular biological activity, immunomodulatory capacity, and mitochondrial function of ADSC. We found that elevated succinate levels in ADSC decreased proliferation and differentiation potential, while promoting M1 macrophage polarization. Furthermore, succinate accumulation impaired mitochondrial biogenesis and metabolism, increasing in reactive oxygen species (ROS) production and inflammatory responses. Transcriptome sequencing analysis further confirmed that succinate upregulated inflammatory pathways, suppressed mitochondrial biogenesis and metabolism, and enhanced cellular apoptosis and senescence, accompanied by reduced DNA replication and repair. Overall, these findings imply that succinate accumulation in ADSC triggers inflammatory response and mitochondrial dysfunction, potentially contributing to a decline of cellular biological activity. Targeting succinate may offer therapeutic potential for metabolic disorders.