DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs

Area of Science:

• Cell Biology
• Neuroscience
• Genetics

Background:

• Mitochondria and peroxisomes are essential organelles undergoing fission regulated by dynamin-related protein 1 (DRP1).
• De novo heterozygous missense mutations in DNM1L cause encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1), a severe neurodevelopmental disorder.
• Current treatments for EMPF1 are lacking, necessitating research into its underlying mechanisms.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms by which DNM1L mutations lead to dysfunction in EMPF1 patients.
• To elucidate the role of mitochondrial dynamics in cellular metabolism and disease pathogenesis.

Main Methods:

• Utilized human-derived fibroblasts from EMPF1 patients.
• Performed morphological analysis of mitochondria and peroxisomes.
• Assessed cellular respiration, mitochondrial membrane potential, and glycolysis.
• Conducted metabolomic analyses to investigate metabolic pathways.

Main Results:

• Patient cells exhibited elongated mitochondrial and peroxisomal morphology with impaired fission.
• Mitochondrial hyperfusion led to aberrant cristae structure and hyperpolarized membrane potential.
• Cells showed reduced coupling efficiency, increased proton leak, upregulated glycolysis, and impaired fatty acid oxidation-dependent respiration.
• Metabolomic analysis revealed defects in the methionine cycle and pyrimidine nucleotide synthesis.

Conclusions:

• DRP1 mutations disrupt mitochondrial and peroxisomal dynamics, leading to significant cellular dysfunction in EMPF1.
• Mitochondrial dynamics are critical for cristae maintenance and cellular metabolic capacity.
• The study provides insights into the pathogenesis of EMPF1, highlighting metabolic derangements and organelle dysfunction.