The amyloid-β-SDR5C1(ABAD) interaction does not mediate a specific inhibition of mitochondrial RNase P

Area of Science:

• Mitochondrial Biology
• Molecular Mechanisms of Disease
• Neuroscience

Background:

• Amyloid-beta (Aβ) is implicated in Alzheimer's disease-related mitochondrial dysfunction.
• The mitochondrial enzyme SDR5C1 (ABAD) binds Aβ, suggesting it mediates toxicity, but the mechanism is unknown.
• SDR5C1 is a component of human mitochondrial RNase P and tRNA:m¹R9 methyltransferase, crucial for tRNA processing.

Purpose of the Study:

• To investigate if SDR5C1's role in tRNA maturation links Aβ to mitochondrial dysfunction.
• To determine if Aβ specifically inhibits SDR5C1-containing tRNA processing enzymes.

Main Methods:

• Recombinant enzyme components were used to test RNase P and methyltransferase activity.
• Enzyme activity was measured upon titration with monomeric or oligomerized Aβ.
• Inhibition assays were performed on both SDR5C1-containing and related enzymes lacking SDR5C1.

Main Results:

• Micromolar concentrations of Aβ inhibited tRNA 5'-end processing and position 9 methylation by SDR5C1-containing enzymes.
• Similar Aβ concentrations also inhibited related RNase P and methyltransferase activities lacking SDR5C1.
• No specific inhibition of SDR5C1-dependent tRNA maturation by Aβ was observed.

Conclusions:

• The proposed deleterious effect of Aβ on mitochondrial function is not explained by specific inhibition of mitochondrial RNase P or its tRNA:m¹R9 methyltransferase subcomplex.
• The molecular mechanism of SDR5C1-mediated Aβ toxicity in Alzheimer's disease remains undetermined.