Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy

Abstract

Tunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection. Additionally, TNTs contribute to acquiring resistance to cancer therapy, probably via their ability to rescue cells by ameliorating various pathological stresses, such as oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, and apoptotic stress. Moreover, mesenchymal stem cells play a crucial role in the rejuvenation of targeted cells with mitochondrial heteroplasmy and oxidative stress by transferring healthy mitochondria through TNTs. Recent research has focussed on uncovering the key regulatory molecules involved in the biogenesis of TNTs. However further work will be required to provide detailed understanding of TNT regulation. In this review, we discuss possible associations with Rho GTPases linked to oxidative stress and apoptotic signals in biogenesis pathways of TNTs and summarize how intercellular trafficking of cargo and organelles, including mitochondria, via TNTs plays a crucial role in disease progression and also in rejuvenation/therapy.

Parameter Identification of 3D Elastic-Plastic Model for Tunnel Engineering Based on Improved Genetic Algorithm

“…Namazi et al used the transverse isotropic constitutive relation to simulate the local deformation behavior of geomaterials in triaxial symmetric compression test, which considered the case of shear zone and pure compression zone [5]. Raghavan et al established an elastic-plastic damage model of geological materials under the framework of continuous thermodynamics, the tensile stress damage is considered in the model, the plastic potential function is based on the Drucker-Prager criterion, and the damage is a function of volumetric strain [6]. Anirban has conducted a lot of systematic research on the elastic-plastic damage constitutive model of rock materials; considering the hydraulic properties of rock under saturated and unsaturated states, an elastic-plastic damage coupled constitutive model of semibrittle materials is established and compared with the experimental results [7].…”

Miro proteins and their role in mitochondrial transfer in cancer and beyond

“…Even though expression of both proteins Miro1 and Miro2 was found elevated in different types of patient tumors, crucial in vitro and in vivo data showing direct involvement of these proteins in the process of horizontal mitochondrial transfer in cancer are still missing. Available data we have are of an indirect character via involvement of Miro in the mitochondrial transport in TNTs (Qin et al, 2021;Raghavan et al, 2021).…”

“…Essential role of Miro in intercellular transfer of mitochondria has been demonstrated by many studies reporting a correlation between Miro expression and mitochondria exchange with TNTs being the conduits for the transport ( Ahmad et al, 2014 ; Babenko et al, 2018 ; English et al, 2020 ; Tseng et al, 2021 ; Wang et al, 2021 ). Except for one study, presence of Miro was found essential for the transfer/movement of mitochondria along TNTs rather than for their formation ( Babenko et al, 2018 ; Raghavan et al, 2021 ). Although direct evidence connecting Miro to a particular alteration in TNT’s dynamic or structure is still missing, the process of TNTs formation via cytoskeleton and membrane remodeling is energetically demanding, with positioning of mitochondria (involving Miro) likely playing a role.…”

“…In cancer, the formation of TNTs and intercellular exchange of mitochondria serves for maintaining the metabolic homeostasis of cancer cells and could be the reason of increased malignancy of cancer cells and cancer drug resistance ( Moschoi et al, 2016 ; Rustom, 2016 ; Marlein et al, 2017 ; Hekmatshoar et al, 2018 ; Sahu et al, 2018 ; Marlein et al, 2019 ; Raghavan et al, 2021 ). One of the first pieces of evidences of TNT formation in malignant tissues comes from solid tumors isolated from patients with lung adenocarcinoma and pleural mesothelioma followed by similar observations in patient-derived ovarian and pancreatic cancer tissues ( Lou et al, 2012b ; Thayanithy et al, 2014 ; Desir et al, 2018 ).…”

“…Later on, mitochondrial transfer via TNTs was observed in glioblastomas, multiple myelomas or in an in vitro model of breast cancer, laryngeal cancer, bladder cancer and others ( Pasquier et al, 2013 ; Antanaviciute et al, 2014 ; Osswald et al, 2015 ; Lu et al, 2017 ; Marlein et al, 2019 ; Pinto et al, 2020 ; Salaud et al, 2020 ; D’Aloia et al, 2021 ; Pinto et al, 2021 ). Similarly, cancer cells have been shown to gain malignancy or enhanced resistance to drug treatment, hypoxia or apoptosis via TNTs ( Pasquier et al, 2013 ; Ady et al, 2014 ; Wang and Gerdes, 2015 ; Desir et al, 2016 ; Rustom, 2016 ; Desir et al, 2018 ; Hekmatshoar et al, 2018 ; Sahu et al, 2018 ; Raghavan et al, 2021 ; Kato et al, 2022 ). Moreover, TNTs were identified in hematological malignancies, where inhibition of their formation improved the survival of diseased mice in vivo and enhanced chemosensitivity in vitro ( Polak et al, 2015 ; Wang et al, 2018 ; Marlein et al, 2019 ).…”