Abstract
The amyloid-β peptide (Aβ) is suggested to cause mitochondrial dysfunction in Alzheimer’s disease. The mitochondrial dehydrogenase SDR5C1 (also known as ABAD) was shown to bind Aβ and was proposed to thereby mediate mitochondrial toxicity, but the molecular mechanism has not been clarified. We recently identified SDR5C1 as an essential component of human mitochondrial RNase P and its associated tRNA:m1R9 methyltransferase, the enzymes responsible for tRNA 5′-end processing and methylation of purines at tRNA position 9, respectively. With this work we investigated whether SDR5C1’s role as a subunit of these two tRNA-maturation activities represents the mechanistic link between Aβ and mitochondrial dysfunction. Using recombinant enzyme components, we tested RNase P and methyltransferase activity upon titration of Aβ. Micromolar concentrations of monomeric or oligomerized Aβ were required to inhibit tRNA 5′-end processing and position 9 methylation catalyzed by the SDR5C1-containing enzymes, yet similar concentrations of Aβ also inhibited related RNase P and methyltransferase activities, which do not contain an SDR5C1 homolog. In conclusion, the proposed deleterious effect of Aβ on mitochondrial function cannot be explained by a specific inhibition of mitochondrial RNase P or its tRNA:m1R9 methyltransferase subcomplex, and the molecular mechanism of SDR5C1-mediated Aβ toxicity remains unclear.
Highlights
Alzheimer’s disease (AD) is the most common form of human dementia
Mitochondrial pool of oligomeric amyloid-b peptide (Ab) was linked to impaired energy metabolism and increased production of reactive oxygen species, and Ab-triggered mitochondrial dysfunction was suggested to be an early and possibly causative event in AD [4,5]
We employed a previously published protocol for ‘‘in vitro ageing’’ to obtain peptide preparations enriched in oligomers [23], and characterized them by polyacrylamide gel electrophoresis (PAGE)
Summary
Alzheimer’s disease (AD) is the most common form of human dementia. Pathological hallmarks of the disease are amyloid plaques composed of the amyloid-b peptide (Ab), neurofibrillary tangles of hyperphosphorylated tau protein and progressive neurodegeneration [1]. Abs are natural products of cellular metabolism, ranging from 39 to 43 amino acids in length; Ab40 is the most abundant form, whereas Ab42 has a stronger propensity to aggregate. The overproduction of Ab or the increased proportion of Ab42 over Ab40 appear sufficient to cause early onset AD [3]. Mitochondrial pool of oligomeric Ab was linked to impaired energy metabolism and increased production of reactive oxygen species, and Ab-triggered mitochondrial dysfunction was suggested to be an early and possibly causative event in AD [4,5]
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