OXPHOS dysfunction regulates integrin-β1 modifications and enhances cell motility and migration

Area of Science:

• Cellular Biology
• Cancer Research
• Mitochondrial Biology

Background:

• Mitochondria are vital for cellular metabolism.
• Mitochondrial oxidative phosphorylation (OXPHOS) dysfunction is linked to cancer progression, including migration, invasion, metastasis, and apoptosis resistance.

Purpose of the Study:

• To investigate the effects of OXPHOS dysfunction in cancer cells.
• To identify molecular players involved in OXPHOS dysfunction-driven cancer cell behaviors.

Main Methods:

• Generated cybrid cell lines with wild-type (WT) or mutant mitochondrial DNA (mtDNA) carrying the A3243T mutation (tRNAmut cybrids).
• Assessed cellular metabolism (oxygen consumption, glucose consumption, lactate production).
• Evaluated cell motility, migration, integrin-β1 N-glycosylation, membrane-bound integrin-β1 levels, fibronectin binding, in vitro growth, and in vivo tumor formation/metastasis in nude mice.

Main Results:

• tRNAmut cybrids showed reduced oxygen consumption and increased glucose consumption/lactate production compared to WT cybrids.
• tRNAmut cybrids exhibited enhanced motility and migration, linked to altered integrin-β1 N-glycosylation (increased β-1,6-GlcNAc branching), higher membrane-bound integrin-β1, and increased fibronectin binding.
• While tRNAmut cybrids had lower in vitro growth rates, they formed larger tumors and showed higher metastatic potential in vivo.

Conclusions:

• mtDNA-driven OXPHOS dysfunction correlates with increased cancer cell motility and migration.
• The mechanism may involve crosstalk between cancer cell mitochondria and the extracellular matrix.
• OXPHOS dysfunction promotes aggressive cancer phenotypes, including enhanced tumor growth and metastasis.