Mitochondrial dysfunction remodels one-carbon metabolism in human cells

Area of Science:

• Biochemistry
• Cell Biology
• Metabolic Disorders

Background:

• Mitochondrial dysfunction underlies various human diseases, from metabolic disorders to neurodegeneration.
• The precise mechanisms linking mitochondrial lesions to cellular pathology remain unclear.
• Proximal consequences of mitochondrial dysfunction in mammalian cells require further investigation.

Purpose of the Study:

• To investigate the link between mitochondrial respiratory chain dysfunction and one-carbon metabolism pathways.
• To elucidate how mitochondrial defects influence metabolic alterations in mammalian cells.

Main Methods:

• Metabolic, proteomic, and transcriptional profiling for hypothesis generation.
• Confirmatory experiments following mitochondrial DNA depletion.
• Assessment of respiratory chain function and formate production from serine.
• Cell growth assays under serine withdrawal with purine or formate supplementation.

Main Results:

• Mitochondrial DNA depletion induced an ATF4-mediated increase in serine biosynthesis and transsulfuration.
• Respiratory chain dysfunction impaired mitochondrial formate production from serine.
• Serine withdrawal caused growth defects in respiratory chain-inhibited cells, rescuable by purine or formate.

Conclusions:

• Mitochondrial respiratory chain function is directly connected to one-carbon metabolism.
• Alterations in serine biosynthesis and formate production are key consequences of mitochondrial dysfunction.
• Findings offer insights into the pathogenesis of mitochondrial disorders.