Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• The mitochondrial matrix integrates proteins from nuclear and mitochondrial genomes, requiring precise folding and assembly.
• The mitochondrial unfolded protein response (UPRmt) in C. elegans senses and responds to matrix protein misfolding.
• Mammalian UPRmt understanding is limited due to a lack of acute activation triggers.

Purpose of the Study:

• To investigate the acute cellular responses to mitochondrial matrix protein misfolding in human cells.
• To analyze the effects of UPRmt activation on mitochondrial translation and protein folding loads.
• To establish a framework for dissecting mammalian UPRmt.

Main Methods:

• Pharmacological inhibition of mitochondrial matrix HSP90/TRAP1 or LON protease to induce UPRmt.
• Global transcriptional and proteomic analysis of human cells.
• Functional studies assessing mitochondrial translation and pre-RNA processing.

Main Results:

• Acute UPRmt activation in human cells induces widespread nuclear gene expression, including matrix proteins for folding, pre-RNA processing, and translation.
• Mitochondrial translation is rapidly and reversibly inhibited during UPRmt.
• Defects in pre-RNA processing occur due to transcriptional repression and LON-dependent turnover of MRPP3.

Conclusions:

• Acute mitochondrial protein folding stress activates both increased chaperone availability and reduced protein synthesis via translational inhibition.
• UPRmt plays a crucial role in maintaining mitochondrial proteostasis under stress.
• This study provides a foundation for further research into mammalian UPRmt mechanisms.