Osteosarcoma is a differentiation-deficient disease

and despite the unique advantages and great potential of differentiation therapy

there are only a few known differentiation inducers

and little research has been done on their targets. Cell differentiation is associated with an increase in mitochondrial content and activity. The metabolism of some tumor cells is characterized by impaired oxidative phosphorylation

as well as up-regulation of aerobic glycolysis and pentose phosphate pathways. Leucine-containing zipper and EF-hand transmembrane protein 1 (LETM1) is involved in the maintenance of mitochondrial morphology and is closely associated with tumorigenesis and progression

as well as cancer cell stemness. We found that MG63 and 143B osteosarcoma cells overexpress LETM1 and exhibit abnormalities in mitochondrial structure and function. Knockdown of LETM1 partially restored the mitochondrial structure and function

inhibited the pentose phosphate pathway

promoted oxidative phosphorylation

and led to osteogenic differentiation. It also inhibited spheroid cell formation

proliferation

migration

and invasion in an

in vitro

model. When LETM1 was knocked down

in vivo

there was reduced tumor formation and lung metastasis. These data suggest that mitochondria are aberrant in LETM1-overexpressing osteosarcoma cells

and knockdown of LETM1 partially restores the mitochondrial structure and function

inhibits the pentose phosphate pathway

promotes oxidative phosphorylation

and increases osteogenic differentiation

thereby reducing malignant biological behavior of the cells.