Int. J. Mol. Sci. 2023, 24 (4), 4085
Translocase of outer mitochondrial membrane 40 (TOMM40) is located in outer membrane of mitochondria. TOMM40 is essential for protein import into mitochondria. TOMM40 genetic variants are believed to increase the risk of Alzheimer’s disease (AD) in different populations. In this study, three exonic variants (rs772262361, rs157581, rs11556505) and three intronic variants (rs157582, rs184017, rs2075650) of TOMM40 gene were identified from Taiwanese AD patients using next-generation sequencing. Associations of three TOMM40 exonic variants and AD susceptibility were further evaluated in another AD cohort. Our results showed that rs157581 (c.339T>C, p.Phe113Leu, F113L) and rs11556505 (c.393C>T, p.Phe131Leu, F131L) were associated with increased risk of AD. We further utilized cell models to examine the role of TOMM40 variation in mitochondrial dysfunction that causes microglial activation and neuroinflammation. When expressed in BV2 microglial cells, AD-associated mutant (F113L) or (F131L) TOMM40-induced mitochondrial dysfunction and oxidative stress-induced activation of microglia and NLRP3 inflammasome. Pro-inflammatory TNF-α, IL-1β and IL-6 released by mutant (F113L) or (F131L) TOMM40-activated BV2 microglial cells caused cell death of hippocampal neurons. Taiwanese AD patients carrying TOMM40 missense (F113L) or (F131L) variants displayed an increased plasma level of inflammatory cytokines IL-6, IL-18, IL-33 and COX-2. Our results provide the evidence that TOMM40 exonic variants, including rs157581 (F113L), and rs11556505 (F131L), increase AD risk of Taiwanese population. Further studies suggest that AD-associated mutant (F113L) or (F131L) TOMM40 cause the neurotoxicity of hippocampal neurons by inducing activation of microglia and NLRP3 inflammasome and release of pro-inflammatory cytokines.
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