AIF3 Splicing Variant Elicits Mitochondrial Malfunction via the Concurrent Dysregulation of Electron Transport Chain and Glutathione-Redox Homeostasis

Authors

Mi Zhou
Shuiqiao Liu
Yanan Wang
Bo Zhang
Ming Zhu
Jennifer E Wang
Veena Rajaram
Yisheng Fang
Weibo Luo
Yingfei Wang

Language

English

Publication Date

2-20-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-57081-5

PMID

39979311

PMCID

PMC11842818

PubMedCentral® Posted Date

2-20-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Child, Apoptosis Inducing Factor, Mitochondrial Diseases, Autopsy, Brain, Mutation, Genetic Variation, RNA Splicing, Animals, Mice, NADH Dehydrogenase, NADP, NAD, Protein Conformation, Reactive Oxygen Species, Glutathione Reductase, Electron Transport, Homeostasis, Male, Female, Infant, Child, Preschool, Calcium-Binding Proteins, Microfilament Proteins, Stress signalling, Molecular neuroscience, Mechanisms of disease, Enzyme mechanisms, RNA splicing

Published Open-Access

yes

Recommended Citation

Zhou, Mi; Liu, Shuiqiao; Wang, Yanan; et al., "AIF3 Splicing Variant Elicits Mitochondrial Malfunction via the Concurrent Dysregulation of Electron Transport Chain and Glutathione-Redox Homeostasis" (2025). Faculty, Staff and Student Publications. 6721.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6721