ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway

Area of Science:

• Biochemistry
• Cell Biology
• Neuroscience

Background:

• Late-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a fatty acid metabolism disorder common in Southern Chinese populations.
• The most frequent mutation is c.250G>A (p.Ala84Thr) in the ETFDH gene, leading to diverse phenotypes including neuropathy and muscle weakness.
• Cellular models of MADD display neurite growth defects and increased apoptosis.

Purpose of the Study:

• To investigate the role of BCL-2 family proteins and mitochondrial pathways in MADD-induced neuronal apoptosis.
• To evaluate the therapeutic potential of coenzyme Q10 in mitigating these cellular defects.

Main Methods:

• Utilized NSC-34 cells with the common ETFDH mutation to model MADD.
• Measured expression levels of proapoptotic proteins (BCL-2 family, cytochrome c, caspases) in mutant vs. wild-type cells.
• Assessed the effect of coenzyme Q10 treatment on protein expression and neurite growth.

Main Results:

• Mutant MADD cells showed elevated levels of proapoptotic proteins (BCL-2-associated X protein, p53-upregulated modulator of apoptosis, cytochrome c, caspase-3, caspase-9).
• Coenzyme Q10 treatment downregulated these activated proteins in mutant cells.
• Coenzyme Q10 treatment also ameliorated neurite growth defects in the MADD cellular model.

Conclusions:

• Activation of the BCL-2/mitochondrial outer membrane permeabilization/apoptosis pathway contributes to neuronal apoptosis in MADD.
• Coenzyme Q10 demonstrates potential as a therapeutic agent to reverse these detrimental effects.
• Findings support the development of new strategies to reduce axonal degeneration and neuronal apoptosis in MADD patients.