Inhibition of mitochondrial OMA1 ameliorates osteosarcoma tumorigenesis

Abstract OMA1 is an ATP-independent zinc metalloprotease that is essential for maintaining mitochondrial homeostasis and plays a vital role in tumorigenesis. Depending on the type of cancer, a decrease in OMA1 expression has been linked to a better or worse prognosis for patients. The role of OMA1 in human osteosarcoma (OS), one of the most prevalent malignant bone tumors, remains elusive. Here, we observed elevated OMA1 expression in OS tumor tissues from two patients with advanced OS. Knockout of OMA1 in OS cells significantly reduces OS tumor weight and size, and lung metastatic nodules in BALB/c nude mice. Immunohistochemistry analysis showed a significant decrease in Ki67 and an increase in cleaved caspase 3 in OMA1 knockout tumor samples. Mechanistically, we found that OMA1 deficiency increases the levels of PINK1 and Parkin, activates mitophagy, induces apoptosis, and reduces cell proliferation and invasion in OS cells. Lack of OMA1 also reduces the amount of cytosolic p53 and p53-associated cytosolic Parkin but increases mitochondrial p53, which may lead to enhanced apoptosis. Furthermore, loss of OMA1 increases cytosolic glycogen synthase kinase 3β (GSK3β) levels, leading to increased interaction between GSK3β and β-catenin and reduced cytosolic and nuclear β-catenin. This contributes, at least in part, to reduced cell proliferation and migration in OMA1-deficient cells. Moreover, we found that ciclopirox (CPX), an antifungal drug, induces OMA1 degradation in cultured OS cells. CPX also reduces tumor development of control OS cells, but does not further reduce tumor development of OMA1-deficient OS cells in mice. These findings strongly support an important role of OMA1 in OS tumorigenesis and suggest that OMA1 may be a valuable prognostic marker for OS and a promising therapeutic target for the treatment of OS.