Intellectual disability-associated factor Zbtb11 cooperates with NRF-2/GABP to control mitochondrial function

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Zbtb11 is a transcription factor linked to hereditary intellectual disability.
• The molecular and cellular functions of Zbtb11 remain largely unknown.
• Understanding Zbtb11's role is key to deciphering the disease's aetiology.

Purpose of the Study:

• To elucidate the molecular and cellular functions of Zbtb11.
• To investigate Zbtb11's role in maintaining mitochondrial homeostasis.
• To understand the pathogenic mechanisms underlying Zbtb11-associated intellectual disability.

Main Methods:

• Functional genomics
• Genetic analysis
• Biochemical assays

Main Results:

• Zbtb11 is essential for mitochondrial function, regulating nuclear genes involved in respiratory complex I and mitoribosome biogenesis.
• Zbtb11 facilitates the recruitment of nuclear respiratory factor 2 (NRF-2) to target promoters.
• Genetic inactivation of Zbtb11 leads to severe complex I assembly defects, impaired respiration, and cell death.
• Pathogenic mutations destabilize Zbtb11, reducing its dosage and downregulating target genes.

Conclusions:

• Zbtb11 is an essential regulator of mitochondrial function and biogenesis.
• This study clarifies nuclear control over mitochondria and the role of Zbtb11 in intellectual disability.