Nuclear localization of MTHFD2 is required for correct mitosis progression

Area of Science:

• Cell Biology
• Biochemistry
• Epigenetics

Background:

• Subcellular compartmentalization of metabolic enzymes creates unique cellular environments.
• Nuclear translocation of metabolic enzymes is essential for epigenetic regulation and gene expression.

Purpose of the Study:

• To investigate the role of the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in nuclear functions.
• To determine the impact of nuclear MTHFD2 on mitosis progression and epigenetic regulation.

Main Methods:

• Investigated the nuclear localization of MTHFD2 using cell-based assays.
• Analyzed protein-protein interactions between nuclear MTHFD2 and mitotic regulators.
• Assessed the effects of MTHFD2 deficiency or altered localization on cell division and chromosome stability.

Main Results:

• Nuclear MTHFD2 interacts with key proteins involved in mitosis regulation and centromere stability, such as KMT5A and DNMT3B.
• Loss of MTHFD2 leads to significant methylation defects, impaired mitosis completion, chromosome congression/segregation errors, and chromosomal aberrations.
• Blocking nuclear MTHFD2 function mimics MTHFD2 deficiency, while nuclear localization alone rescues mitotic progression.

Conclusions:

• MTHFD2 has a critical nuclear function in ensuring accurate mitosis progression.
• Nuclear translocation of metabolic enzymes like MTHFD2 is necessary to fulfill specific chromatin requirements.
• This study reveals a novel nuclear role for a mitochondrial enzyme, expanding our understanding of metabolic enzyme function beyond the cytoplasm.