Abstract
During pathogenesis of Alzheimer’s disease (AD), mitochondria suffer alterations that lead to low energy production and reactive oxygen species formation. However, the mechanism of impaired mitochondria homeostasis in AD is not fully understood. We hypothesized that abnormal sphingolipid metabolism in mitochondria could be one of the contributing factors to mitochondrial dysfunction. Synaptic and non-synaptic mitochondria were isolated from 5xFAD and wild type (WT) mice at 3 and 7 months using Ficoll gradient ultracentrifugation, and their function was analyzed using Seahorse assay. Additionally, mitochondria were ana- lyzed using mass spectrometry for proteomics and sphingolipidomics analyses. Sphingolipid levels were also determined in synaptic and non-synaptic mitochondria isolated from AD patients and healthy controls. We found that synaptic mitochondria isolated from 3-months old 5xFAD mice manifest diminished oxygen consumption as compared to WT. Consistently, proteomics analysis showed that proteins related to respiratory electron transport and oxida- tive phosphorylation were altered in 5xFAD mice. When quantifying the main sphingolipids in mitochondria, we found that Cer 18:0, Cer 22:0, and Cer 24:1 were increased already at 3 months in 5xFAD mice. No increase in ceramides was detected in mitochondria isolated from AD patients. However, increased levels of sphingosine were found in both 5xFAD mice and AD patients when compared to respective controls. We report that the regulation of sphingolipids in mitochondria is abnormal at 3 months of age in 5xFAD mice, as indicated by the accumulation of long-chain ceramides, which increases with age. Sphingosine levels are increased in both the mitochondria of 5xFAD mice and AD patients. Our data suggest that the sphingolipid composition is dysregulated in mitochondria early during AD pathogenesis.
Document Type
Article
Publication Date
2024
Digital Object Identifier (DOI)
https://doi.org/10.1080/17590914.2024.2404367
Funding Information
This work was supported by grants to EB (National Institutes of Health: R01AG064234, R21AG078601, RF1AG078338; U.S. Department of Veterans Affairs: I01BX003643) and to SMC (BrightFocus Grant Submission Number: A20201464F; National Institute on Aging of the National Institutes of Health under Award Number P30AG028383). PGS and HV received support from Kentucky Spinal Cord and Head Injury Research Trust (KSCHIRT chair #3).
Repository Citation
Crivelli, Simone M.; Quadri, Zainuddin; Elsherbini, Ahmed; Vekaria, Hemendra J.; Sullivan, Patrick G.; Zhi, Wenbo; Martinez-Martinez, Pilar; Spassieva, Stefka D.; and Bieberich, Erhard, "Abnormal Regulation of Mitochondrial Sphingolipids during Aging and Alzheimer’s Disease" (2024). Markey Cancer Center Faculty Publications. 248.
https://uknowledge.uky.edu/markey_facpub/248
Notes/Citation Information
© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.