Abnormal Regulation of Mitochondrial Sphingolipids during Aging and Alzheimer's Disease.

IF 3.9 4区 医学 Q2 NEUROSCIENCES
ASN NEURO Pub Date : 2024-01-01 Epub Date: 2024-11-05 DOI:10.1080/17590914.2024.2404367
Simone M Crivelli, Zainuddin Quadri, Ahmed Elsherbini, Hemendra J Vekaria, Patrick G Sullivan, Wenbo Zhi, Pilar Martinez-Martinez, Stefka D Spassieva, Erhard Bieberich
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引用次数: 0

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 analyzed 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 oxidative 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.

衰老和阿尔茨海默病过程中线粒体鞘磷脂的异常调节
在阿尔茨海默病(AD)的发病过程中,线粒体会发生改变,导致能量产生不足和活性氧形成。然而,阿尔茨海默病线粒体平衡受损的机制尚未完全明了。我们推测,线粒体中异常的鞘脂代谢可能是导致线粒体功能障碍的因素之一。我们使用 Ficoll 梯度超速离心法从 5xFAD 和野生型(WT)小鼠 3 个月和 7 个月时分离出突触线粒体和非突触线粒体,并使用海马测定法分析它们的功能。此外,还使用质谱分析线粒体的蛋白质组学和鞘脂组学。我们还测定了从AD患者和健康对照组分离的突触线粒体和非突触线粒体中的鞘脂水平。我们发现,与 WT 小鼠相比,从 3 个月大的 5xFAD 小鼠体内分离出的突触线粒体耗氧量减少。同时,蛋白质组学分析表明,5xFAD 小鼠体内与呼吸电子传递和氧化磷酸化相关的蛋白质发生了改变。在量化线粒体中的主要鞘脂时,我们发现 5xFAD 小鼠 3 个月大时,Cer 18:0、Cer 22:0 和 Cer 24:1 已经增加。从 AD 患者体内分离出的线粒体中未检测到神经酰胺的增加。然而,与各自的对照组相比,5xFAD 小鼠和 AD 患者体内的鞘磷脂水平都有所增加。我们报告称,5xFAD 小鼠在 3 个月大时线粒体中的鞘磷脂调节出现异常,表现为长链神经酰胺的积累,且随着年龄的增长而增加。在 5xFAD 小鼠和 AD 患者的线粒体中,鞘磷脂的水平都有所增加。我们的数据表明,在 AD 发病早期,线粒体中的鞘脂组成就已经失调。
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来源期刊
ASN NEURO
ASN NEURO NEUROSCIENCES-
CiteScore
7.70
自引率
4.30%
发文量
35
审稿时长
>12 weeks
期刊介绍: ASN NEURO is an open access, peer-reviewed journal uniquely positioned to provide investigators with the most recent advances across the breadth of the cellular and molecular neurosciences. The official journal of the American Society for Neurochemistry, ASN NEURO is dedicated to the promotion, support, and facilitation of communication among cellular and molecular neuroscientists of all specializations.
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