Age-specific and compartment-dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Aging Cell Pub Date : 2024-06-17 DOI:10.1111/acel.14250
James N. Sleigh, Francesca Mattedi, Sandy Richter, Emily Annuario, Kristal Ng, I. Emilie Steinmark, Iveta Ivanova, István L. Darabán, Parth P. Joshi, Elena R. Rhymes, Shirwa Awale, Gokhan Yahioglu, Jacqueline C. Mitchell, Klaus Suhling, Giampietro Schiavo, Alessio Vagnoni
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Abstract

Mitochondria are dynamic bioenergetic hubs that become compromised with age. In neurons, declining mitochondrial axonal transport has been associated with reduced cellular health. However, it is still unclear to what extent the decline of mitochondrial transport and function observed during ageing are coupled, and if somal and axonal mitochondria display compartment-specific features that make them more susceptible to the ageing process. It is also not known whether the biophysical state of the cytoplasm, thought to affect many cellular functions, changes with age to impact mitochondrial trafficking and homeostasis. Focusing on the mouse peripheral nervous system, we show that age-dependent decline in mitochondrial trafficking is accompanied by reduction of mitochondrial membrane potential and intramitochondrial viscosity, but not calcium buffering, in both somal and axonal mitochondria. Intriguingly, we observe a specific increase in cytoplasmic viscosity in the neuronal cell body, where mitochondria are most polarised, which correlates with decreased cytoplasmic diffusiveness. Increasing cytoplasmic crowding in the somatic compartment of DRG neurons grown in microfluidic chambers reduces mitochondrial axonal trafficking, suggesting a mechanistic link between the regulation of cytoplasmic viscosity and mitochondrial dynamics. Our work provides a reference for studying the relationship between neuronal mitochondrial homeostasis and the viscoelasticity of the cytoplasm in a compartment-dependent manner during ageing.

Abstract Image

Abstract Image

小鼠外周神经元线粒体稳态和胞质粘度的变化具有年龄特异性和分区依赖性。
线粒体是充满活力的生物能枢纽,但随着年龄的增长,它的功能会受到损害。在神经元中,线粒体轴突运输的下降与细胞健康的降低有关。然而,目前还不清楚在衰老过程中观察到的线粒体转运和功能下降在多大程度上是相互关联的,也不清楚体细胞和轴突线粒体是否显示出特定的区室特征,使它们更容易受到衰老过程的影响。此外,人们还不知道被认为会影响许多细胞功能的细胞质的生物物理状态是否会随着年龄的增长而发生变化,从而影响线粒体的转运和平衡。我们以小鼠外周神经系统为研究对象,发现线粒体运输随年龄增长而下降的同时,体细胞和轴突线粒体的线粒体膜电位和线粒体内粘度也在降低,但钙缓冲作用却没有降低。有趣的是,我们在线粒体极化程度最高的神经元细胞体中观察到细胞质粘度的特定增加,这与细胞质扩散性的降低有关。在微流体室中生长的 DRG 神经元体细胞室中细胞质拥挤程度的增加会减少线粒体轴突的贩运,这表明细胞质粘度的调节与线粒体动力学之间存在机理联系。我们的研究为研究神经元线粒体稳态与细胞质粘弹性之间的关系提供了参考。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
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