Different mtDNA mutations modify tumor progression in dependence of the degree of respiratory complex I impairment

Area of Science:

• Oncology
• Mitochondrial Biology
• Cancer Genetics

Background:

• Mitochondrial DNA (mtDNA) mutations are prevalent in cancer, particularly affecting mitochondrial complex I (CI) genes.
• The precise role of mtDNA mutations in tumor progression (pro- or anti-tumorigenic) remains incompletely understood.
• Osteosarcoma is a common bone cancer where mtDNA mutations are being investigated for their impact on aggressiveness.

Purpose of the Study:

• To investigate the impact of specific homoplasmic mtDNA mutations (m.3460G>A/MT-ND1, m.3571insC/MT-ND1, and m.3243A>G/MT-TL1) on osteosarcoma progression.
• To determine if the degree of oxidative phosphorylation (OXPHOS) impairment influences the tumorigenic potential of osteosarcoma cells.
• To elucidate the mechanisms by which mtDNA mutations affect tumor growth, including metabolic and signaling pathway alterations.

Main Methods:

• Analysis of three homoplasmic mtDNA mutations in osteosarcoma cells, selected for varying degrees of CI dysfunction.
• Assessment of CI activity, OXPHOS function, and cellular energy metabolism (glycolysis, AMP-activated protein kinase activation).
• Evaluation of osteosarcoma cell tumorigenic potential in vitro and in vivo, correlating with mtDNA mutation severity and hypoxia-inducible factor 1α (HIF-1α) stabilization.

Main Results:

• The m.3460G>A/MT-ND1 mutation caused mild CI activity reduction, while m.3571insC/MT-ND1 and m.3243A>G/MT-TL1 induced severe CI structural and functional defects.
• Severe CI dysfunction led to an energetic deficit, compensatory glycolysis increase, and AMP-activated protein kinase activation.
• Osteosarcoma cells with severe CI impairment exhibited significantly reduced in vitro and in vivo tumorigenic potential compared to cells with mild CI dysfunction.
• Tumor growth modulation was independent of reactive oxygen species (ROS) but correlated with HIF-1α stabilization.

Conclusions:

• The impact of mtDNA mutations on osteosarcoma tumorigenicity is dependent on the type and severity of the resulting OXPHOS dysfunction.
• Severe impairment of CI and OXPHOS function can reduce osteosarcoma's tumorigenic potential.
• Structural and functional integrity of CI and OXPHOS are crucial for hypoxic adaptation and osteosarcoma progression, mediated through HIF-1α stabilization.