Suppression of Mic60 compromises mitochondrial transcription and oxidative phosphorylation

Area of Science:

• Mitochondrial biology
• Molecular genetics
• Cellular respiration

Background:

• Precise regulation of mitochondrial DNA (mtDNA) transcription and oxidative phosphorylation (OXPHOS) is vital for human health.
• Mic60, a component of the MICOS complex, is known for its role in mitochondrial morphology, but its function in mtDNA transcription is unexplored.

Purpose of the Study:

• To investigate the role of Mic60 in mitochondrial transcription and its potential interaction with transcription factors.
• To determine if Mic60 influences the regulation of OXPHOS activities.

Main Methods:

• Co-immunoprecipitation assays to detect protein-protein interactions.
• Mic60 knockdown experiments to assess effects on mtDNA transcription and OXPHOS.
• mtDNA immunoprecipitation (mIP)-chromatin conformation capture (3C) assays to analyze Mic60's interaction with mtDNA and its role in the D-loop region architecture.

Main Results:

• Mic60 was found to interact with mitochondrial transcription factors TFAM and TFB2M.
• Mic60 knockdown led to compromised mtDNA transcription and reduced OXPHOS activity.
• Mic60 deficiency impaired TFAM binding and POLRMT recruitment to mtDNA promoters, and Mic60 was involved in the mtDNA D-loop region architecture.

Conclusions:

• Mic60 plays a crucial, previously unrecognized role in regulating mtDNA transcription.
• The interaction of Mic60 with TFAM, TFB2M, and mtDNA is essential for efficient transcription and OXPHOS.
• Mic60 is a key regulator linking mitochondrial morphology to gene expression and energy metabolism.