Bezafibrate partially rescues mitochondrial dysfunction in NDUFAF2-deficient cellular and rotenone-induced models of complex I impairment
Year: 2026
Type: article
Abstract: Background Leigh syndrome (LS) is a devastating mitochondrial encephalopathy caused by impaired oxidative phosphorylation and consequent bioenergetic failure. As NDUFAF2 is a critical assembly factor for mitochondrial complex I, we investigated whether NDUFAF2 deficiency contributes to fibroblast dysfunction and whether bezafibrate can ameliorate the associated pathological phenotypes. Results Stable knockdown of NDUFAF2 in L929 fibroblasts impaired cell viability, promoted apoptosis, and caused marked mitochondrial dysfunction, whereas bezafibrate partially rescued these abnormalities. To determine whether the protective effects of bezafibrate extended to an in vivo setting of pharmacological complex I inhibition, we further examined rotenone-treated mice. Rotenone exposure induced an LS-like phenotype characterized by weight loss, decreased food and water intake, motor dysfunction, and shortened survival, all of which were significantly attenuated by bezafibrate treatment. Mechanistically, bezafibrate improved mitochondrial function in fibroblast-enriched clusters within brain tissue, restored molecular features associated with complex I homeostasis, and reshaped disease-associated pathways related to neuroactive ligand-receptor interactions and receptor-mediated mitophagy. Targeted validation further supported the involvement of the MCHR1/CRHR2-cAMP axis and mitophagy-related remodeling. Conclusions These findings indicate that NDUFAF2-dependent mitochondrial homeostasis in fibroblasts is an important and previously underappreciated contributor to LS-like pathology. These findings suggest that bezafibrate may have therapeutic potential in experimental models of mitochondrial complex I dysfunction and warrant further investigation in genetically defined disease models.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,990
OpenAlex ID: W7225792712
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