AIF3 splicing variant elicits mitochondrial malfunction via the concurrent dysregulation of electron transport chain and glutathione-redox homeostasis

Mi Zhou, Shuiqiao Liu, Yanan Wang, Bo Zhang, Ming Zhu, Jennifer E. Wang, Veena Rajaram, Yisheng Fang, Weibo Luo and Yingfei Wang ()
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Mi Zhou: University of Texas Southwestern Medical Center
Shuiqiao Liu: University of Texas Southwestern Medical Center
Yanan Wang: University of Texas Southwestern Medical Center
Bo Zhang: University of Texas Southwestern Medical Center
Ming Zhu: University of Texas Southwestern Medical Center
Jennifer E. Wang: University of Texas Southwestern Medical Center
Veena Rajaram: University of Texas Southwestern Medical Center
Yisheng Fang: University of Texas Southwestern Medical Center
Weibo Luo: University of Texas Southwestern Medical Center
Yingfei Wang: University of Texas Southwestern Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Genetic mutations in apoptosis-inducing factor (AIF) have a strong association with mitochondrial disorders; however, little is known about the aberrant splicing variants in affected patients and how these variants contribute to mitochondrial dysfunction and brain development defects. We identified pathologic AIF3/AIF3-like splicing variants in postmortem brain tissues of pediatric individuals with mitochondrial disorders. Mutations in AIFM1 exon-2/3 increase splicing risks. AIF3-splicing disrupts mitochondrial complexes, membrane potential, and respiration, causing brain development defects. Mechanistically, AIF is a mammalian NAD(P)H dehydrogenase and possesses glutathione reductase activity controlling respiratory chain functions and glutathione regeneration. Conversely, AIF3, lacking these activities, disassembles mitochondrial complexes, increases ROS generation, and simultaneously hinders antioxidant defense. Expression of NADH dehydrogenase NDI1 restores mitochondrial functions partially and protects neurons in AIF3-splicing mice. Our findings unveil an underrated role of AIF as a mammalian mitochondrial complex-I alternative NAD(P)H dehydrogenase and provide insights into pathologic AIF-variants in mitochondrial disorders and brain development.

Date: 2025
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DOI: 10.1038/s41467-025-57081-5

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