HMGA2 mediates Cr (VI)-induced metabolic reprogramming through binding to mitochondrial D-Loop region

Area of Science:

• Cellular metabolism
• Carcinogenesis
• Environmental toxicology

Background:

• Hexavalent chromium (Cr (VI)) is an occupational and environmental carcinogen.
• Metabolic reprogramming, shifting from oxidative phosphorylation (OXPHOS) to glycolysis, is a hallmark of cancer.
• The role of High Mobility Group A2 (HMGA2) in Cr (VI)-induced metabolic changes remains unclear.

Purpose of the Study:

• To investigate the role of HMGA2 in Cr (VI)-induced metabolic reprogramming from OXPHOS to glycolysis.
• To elucidate the mechanisms underlying HMGA2 involvement in Cr (VI) toxicity.
• To explore the interplay between mitochondrial dysfunction, ER stress, and HMGA2 in Cr (VI) exposure.

Main Methods:

• Cell culture (A549 and HELF cells)
• siRNA-mediated knockdown and DNA plasmid transfection for HMGA2 manipulation
• Western blotting for OXPHOS proteins (COX IV, ND1)
• Mitochondrial mass assessment
• Mitochondrial function inhibitor (CCCP) and ER stress inhibitor (4-PBA) treatments
• Chromatin immunoprecipitation (ChIP) assay for HMGA2 binding to mitochondrial DNA (mtDNA)

Main Results:

• Knockdown of HMGA2 attenuated Cr (VI)-induced reduction in OXPHOS proteins and mitochondrial mass.
• Overexpression of HMGA2 decreased OXPHOS protein expression and mitochondrial mass.
• Mitochondrial dysfunction and ER stress inhibitors reduced HMGA2 levels, indicating their role in Cr (VI)-induced HMGA2 expression.
• Cr (VI) exposure led to HMGA2 accumulation in mitochondria, with ChIP confirming HMGA2 binding to the mtDNA D-loop region.
• The ER stress/HMGA2 axis mediated the metabolic shift from OXPHOS to aerobic glycolysis.

Conclusions:

• Cr (VI) exposure induces metabolic reprogramming from OXPHOS to glycolysis via an ER stress- and mitochondria-enhanced HMGA2 pathway.
• HMGA2 directly modulates OXPHOS by binding to the mtDNA D-loop region.
• This study provides insights into the mechanism of Cr (VI) carcinogenicity, highlighting the contribution of metabolic disruption.