Rnd3 Expression is Necessary to Maintain Mitochondrial Homeostasis but Dispensable for Autophagy

Abstract

Autophagy is a highly conserved process that mediates the targeting and degradation of intracellular components to lysosomes, contributing to the maintenance of cellular homeostasis and to obtaining energy, which ensures viability under stress conditions. Therefore, autophagy defects are common to different neurodegenerative disorders. Rnd3 belongs to the family of Rho GTPases, involved in the regulation of actin cytoskeleton dynamics and important in the modulation of cellular processes such as migration and proliferation. Murine models have shown that Rnd3 is relevant for the correct development and function of the Central Nervous System and lack of its expression produces several motor alterations and neural development impairment. However, little is known about the molecular events through which Rnd3 produces these phenotypes. Interestingly we have observed that Rnd3 deficiency correlates with the appearance of autophagy impairment profiles and irregular mitochondria. In this work, we have explored the impact of Rnd3 loss of expression in mitochondrial function and autophagy, using a Rnd3 KO CRISPR cell model. Rnd3 deficient cells show no alterations in autophagy and mitochondria turnover is not impaired. However, Rnd3 KO cells have an altered mitochondria oxidative metabolism, resembling the effect caused by oxidative stress. In fact, lack of Rnd3 expression makes these cells strictly dependent on glycolysis to obtain energy. Altogether, our results demonstrate that Rnd3 is relevant to maintain mitochondria function, suggesting a possible relationship with neurodegenerative diseases.

The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomics

“…We also noted expression selectively in LC-NE neurons of a number of genes whose expression is altered in animal models or in human disease in the LC (SSTR2, PHOX2A, PHOX2A) [45,46]. We identified LC enrichment of a number of genes that have been associated at the cellular level with apoptosis, cell loss, or pathology in the context of neurodegeneration (RND3, P2RY1) [47][48][49][50]. We also noted enrichment of NT5DC2 in LC, a gene which has been associated with attention-deficit hyperactivity disorder (ADHD) and regulates catecholamine synthesis in vitro [51,52].…”

The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomics

“…We also noted expression selectively in LC-NE neurons of a number of genes whose expression is altered in animal models or in human disease in the LC ( SSTR2 , PHOX2A , PHOX2B ) ( Fan et al, 2018 ; Ádori et al, 2015 ). We identified LC enrichment of a number of genes that have been associated at the cellular level with apoptosis, cell loss, or pathology in the context of neurodegeneration ( RND3 , P2RY1 ) ( Pietrowski et al, 2021 ; Moore et al, 2000 ; Cueto-Ureña et al, 2022 ; Dong et al, 2021 ). We also noted enrichment of NT5DC2 in the LC, a gene which has been associated with ADHD and regulates catecholamine synthesis in vitro ( van Hulzen et al, 2017 ; Nakashima et al, 2019 ).…”

RND3 Potentiates Proinflammatory Activation through NOTCH Signaling in Activated Macrophages

“…Different studies have identified RND3 as a protective factor for mitochondrial function; indeed, the absence of RND3 activity has been related with altered mitochondria oxidative metabolism, favoring dependence of cells on glycolysis to obtain energy [42,43]. In other cellular models, the absence of RND3 has been related with an increase of ROS generation and mitochondria dysfunction; moreover, a physical interaction between PPARγ and RND3 has been described to potentiate mitochondrial function [44].…”