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

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 t

SUBMITTER: Zhou M 

PROVIDER: S-EPMC11842818 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature