STING regulates aging-related osteoporosis by mediating the Hk2-Vdac1 mitochondrial axis

Metabolic abnormalities and mild inflammation are hallmarks of aging and major driving factors for aging-related damage and bone metabolic diseases. Mitochondria are crucial links in energy metabolism and immune homeostasis regulation. Mitochondrial dysfunction is considered one of the pathogenic factors of aging-related osteoporosis, but its mechanism of action needs further research. Here, we demonstrated that the interaction between stimulator of interferon genes (STING)-mediated regulation of hexokinase 2 (Hk2)-voltage-dependent anion channel-1 (Vdac1) is a critical factor contributing to mitochondrial dysfunction and osteogenic abnormalities during aging. As the aging process progresses, factors related to aging cause an increase in STING expression, which disrupts the interaction between Hk2 and Vdac1. Dissociation of Hk2 from Vadc1 triggered the opening of the mitochondrial inner mitochondrial permeability transition pore (mPTP), leading to mitochondrial dysfunction and abnormal osteogenic differentiation, thereby disrupting bone homeostasis. In brief, this study demonstrates that STING acts as an intracellular metabolic Checkpoint, influencing mitochondrial function to promote the development of osteoporosis. These findings significantly enhance the development of STING-targeted treatments for aging-related osteoporosis. RNA-seq profiling of bone marrow-derived mesenchymal stem cells (BM-MSCs) from 4-week-old control (n = 3) and shVdac1 (n = 3) male C57BL/6 mice.