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

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.

• Authors: Kahli Zeitlow, Lefko Charlambous, Isaac Ng, Sonal Gagrani, Mirta Mihovilovic, Shuhong Luo, Daniel L Rock, Ann Saunders, Allen D Roses, W Kirby Gottschalk
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1863 Issue 11 Pg. 2973-2986 (11 2017) ISSN: 0925-4439 [Print] Netherlands
• PMID: 28768149 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Apolipoproteins E
• HSP70 Heat-Shock Proteins
• HSPA9 protein, human
• Membrane Transport Proteins
• Mitochondrial Precursor Protein Import Complex Proteins
• Mitochondrial Proteins
• Receptors, Cell Surface
• TOMM20 protein, human
• TOMM40 protein, human
• Ketoglutarate Dehydrogenase Complex
• Electron Transport Complex I

Topics

• Alzheimer Disease (genetics, metabolism, pathology)
• Apolipoproteins E (genetics, metabolism)
• Electron Transport Complex I (genetics, metabolism)
• Female
• Gene Expression Regulation
• Genetic Loci
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• HeLa Cells
• Humans
• Ketoglutarate Dehydrogenase Complex (genetics, metabolism)
• Membrane Potential, Mitochondrial (genetics)
• Membrane Transport Proteins (biosynthesis, genetics)
• Mitochondria (genetics, metabolism, pathology)
• Mitochondrial Precursor Protein Import Complex Proteins
• Mitochondrial Proteins (genetics, metabolism)
• Receptors, Cell Surface (biosynthesis, genetics)