Poster #045
Polyamine Imbalance Impairs MSC Mitochondrial Secretion During Osteogenesis
Mentors: Bryan Le, PhD; PI: Fernando Fierro, PhD
Snyder-Robinson Syndrome (SRS)—a rare X-linked disease characterized by skeletal abnormalities including childhood osteoporosis—is caused by loss-of-function mutations in the SMS gene, which encodes for spermine synthase (Sms), leading to low spermine and high spermidine levels. While SRS pathogenesis remains unclear, Sms deficiency alters the function and morphology of mitochondria, which, besides generating energy, play a critical role in precipitating calcium phosphate and are secreted for bone mineralization. Notably, spermidine serves as the substrate for hypusinated-eIF5a, which is critical for mitochondrial function. We hypothesize that Sms deficiency impairs mitochondrial secretion, which is rescued by inhibiting hypusinated-eIF5a using N1-guanyl-1,7-diaminoheptane (GC7). We treated human bone marrow-derived mesenchymal stem cells with cyclohexyldiaminopropane (CDAP) to inhibit Sms. CDAP-treated cells have impaired mitochondrial secretion and calcium phosphate accumulation, which GC7 can rescue. Thus, mitochondria are likely essential in SRS pathogenesis and serve a non-traditional role in bone mineralization, holding profound implications in bone-related health.