The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

Kahli Zeitlow, Lefko Charlambous, Isaac Ng, Sonal Gagrani, Mirta Mihovilovic, Shuhong Luo, Daniel L. Rock, Ann Saunders, Allen D. Roses, W. Kirby Gottschalk

Research output: Contribution to journalArticle

Abstract

A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of-onset of sporadic (late-onset) Alzheimer's disease. In Caucasians, the three predominant alleles at this locus are Short (S), Long (L) or Very long (VL). On an APOE ε3/3 background, the S/VL and VL/VL genotypes are more protective than S/S. The '523 poly-T has regulatory properties, in that the VL poly-T results in higher expression than the S poly-T in luciferase expression systems. The aim of the current work was to identify effects on cellular bioenergetics of increased TOM40 protein expression. MitoTracker Green fluorescence and autophagic vesicle staining was the same in control and over-expressing cells, but TOM40 over-expression was associated with increased expression of TOM20, a preprotein receptor of the TOM complex, the mitochondrial chaperone HSPA9, and PDHE1a, and increased activities of the oxidative phosphorylation complexes I and IV and of the TCA member α-ketoglutaric acid dehydrogenase. Consistent with the complex I findings, respiration was more sensitive to inhibition by rotenone in control cells than in the TOM40 over-expressing cells. In the absence of inhibitors, total cellular ATP, the mitochondrial membrane potential, and respiration were elevated in the over-expressing cells. Spare respiratory capacity was greater in the TOM40 over-expressing cells than in the controls. TOM40 over-expression blocked Ab-elicited decreases in the mitochondrial membrane potential, cellular ATP levels, and cellular viability in the control cells. These data suggest elevated expression of TOM40 may be protective of mitochondrial function.

Original languageEnglish (US)
Pages (from-to)2973-2986
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1863
Issue number11
DOIs
StatePublished - Nov 2017

Keywords

  • Alzheimer's
  • Energetics
  • Mitochondria
  • Neurodegeneration
  • TOM
  • TOMM40

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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  • Cite this

    Zeitlow, K., Charlambous, L., Ng, I., Gagrani, S., Mihovilovic, M., Luo, S., Rock, D. L., Saunders, A., Roses, A. D., & Gottschalk, W. K. (2017). The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1863(11), 2973-2986. https://doi.org/10.1016/j.bbadis.2017.07.031