FOXM1 nuclear transcription factor translocates into mitochondria and inhibits oxidative phosphorylation

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Forkhead box M1 (FOXM1) is a nuclear transcription factor crucial for cell cycle regulation and highly expressed in many human cancers.
• The non-transcriptional functions of FOXM1, particularly its role outside the nucleus, remain largely unexplored.

Purpose of the Study:

• To investigate the potential extranuclear functions of FOXM1.
• To determine if FOXM1 has a role within mitochondria and its impact on mitochondrial function.

Main Methods:

• Utilized site-directed mutagenesis to create FOXM1 mutants with specific subcellular localizations (nuclear vs. mitochondrial).
• Assessed mitochondrial function including mass, membrane potential, respiration, and electron transport chain (ETC) activity.
• Performed co-immunoprecipitation and binding assays to identify protein interactions within mitochondria.

Main Results:

• FOXM1 protein was detected within mitochondria.
• Mitochondrial localization of FOXM1 led to decreased mitochondrial mass, membrane potential, respiration, and ETC activity.
• FOXM1 directly bound to and increased levels of pentatricopeptide repeat domain 1 (PTCD1) in mitochondria, inhibiting ETC complexes.
• Mitochondrial FOXM1 did not affect cellular proliferation rates.

Conclusions:

• FOXM1 translocates to mitochondria and inhibits mitochondrial respiration through interaction with PTCD1.
• This study reveals a novel, transcription-independent function of FOXM1 in regulating mitochondrial homeostasis.