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

• Published in: Scientific reports 2024-10, Vol.14 (1), p.25374-10, Article 25374
• Main Authors: Lin, Chuang-Yu, Liang, Wen-Chen, Yu, Yi-Chen, Chang, Shin-Cheng, Lai, Ming-Chi, Jong, Yuh-Jyh
• Format: Article
• Language: English
• Subjects: 631/378; 692/4017; 692/617; Animals; Apoptosis; Apoptosis - genetics; Axonogenesis; Bcl-2 protein; Bcl-x protein; Carnitine; Caspase-3; Caspase-9; Cell activation; Cell culture; Cell Line; Coenzyme A; Coenzyme Q10; Cytochrome c; Dehydrogenase; Dehydrogenases; Electron transfer; Electron-Transferring Flavoproteins - genetics; Electron-Transferring Flavoproteins - metabolism; ETFDH; Humanities and Social Sciences; Humans; Iron-Sulfur Proteins - genetics; Iron-Sulfur Proteins - metabolism; Lymphocytes B; Lymphoma; Mice; multidisciplinary; Multiple Acyl Coenzyme A Dehydrogenase Deficiency - genetics; Multiple Acyl Coenzyme A Dehydrogenase Deficiency - metabolism; Multiple acyl-coenzyme A dehydrogenase deficiency; Mutants; Mutation; Neurodegeneration; Neuronal Outgrowth; Oxidoreductases Acting on CH-NH Group Donors - genetics; Oxidoreductases Acting on CH-NH Group Donors - metabolism; p53 Protein; Peripheral neuropathy; Phenotypes; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rhabdomyolysis; Riboflavin; Science; Science (multidisciplinary); Signal Transduction; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-75286-4

The most common mutation in southern Chinese individuals with late-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD; a fatty acid metabolism disorder) is c.250G > A (p.Ala84Thr) in the electron transfer flavoprotein dehydrogenase gene ( ETFDH ). Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts. Our cellular models of MADD exhibit neurite growth defects and excessive apoptosis. Given that axonal degeneration and neuronal apoptosis may be regulated by B-cell lymphoma (BCL)-2 family proteins and mitochondrial outer membrane permeabilization through the activation of proapoptotic molecules, we measured the expression levels of proapoptotic BCL-2 family proteins (e.g., BCL-2-associated X protein and p53-upregulated modulator of apoptosis), cytochrome c, caspase-3, and caspase-9 in NSC-34 cells carrying the most common ETFDH mutation. The levels of these proteins were higher in the mutant cells than in the wide-type cells. Subsequent treatment of the mutant cells with coenzyme Q10 downregulated activated protein expression and mitigated neurite growth defects. These results suggest that the activation of the BCL-2/mitochondrial outer membrane permeabilization/apoptosis pathway promotes apoptosis in cellular models of MADD and that coenzyme Q10 can reverse this effect. Our findings aid the development of novel therapeutic strategies for reducing axonal degeneration and neuronal apoptosis in MADD.