Horizontal mitochondrial transfer as a novel bioenergetic tool for mesenchymal stromal/stem cells: molecular mechanisms and therapeutic potential in a variety of diseases

Abstract

Intercellular mitochondrial transfer (MT) is a newly discovered form of cell-to-cell signalling involving the active incorporation of healthy mitochondria into stressed/injured recipient cells, contributing to the restoration of bioenergetic profile and cell viability, reduction of inflammatory processes and normalisation of calcium dynamics. Recent evidence has shown that MT can occur through multiple cellular structures and mechanisms: tunneling nanotubes (TNTs), via gap junctions (GJs), mediated by extracellular vesicles (EVs) and other mechanisms (cell fusion, mitochondrial extrusion and migrasome-mediated mitocytosis) and in different contexts, such as under physiological (tissue homeostasis and stemness maintenance) and pathological conditions (hypoxia, inflammation and cancer). As Mesenchimal Stromal/ Stem Cells (MSC)-mediated MT has emerged as a critical regulatory and restorative mechanism for cell and tissue regeneration and damage repair in recent years, its potential in stem cell therapy has received increasing attention. In particular, the potential therapeutic role of MSCs has been reported in several articles, suggesting that MSCs can enhance tissue repair after injury via MT and membrane vesicle release. For these reasons, in this review, we will discuss the different mechanisms of MSCs-mediated MT and therapeutic effects on different diseases such as neuronal, ischaemic, vascular and pulmonary diseases. Therefore, understanding the molecular and cellular mechanisms of MT and demonstrating its efficacy could be an important milestone that lays the foundation for future clinical trials.

Keywords: Extracellular vesicles; Horizontal mitochondrial transfer; Ischemic vascular diseases; Mesenchymal Stromal/Stem cells; Mitochondria; Neuronal diseases; Tunnelling nanotubes.

Fig. 1

Different mechanisms and routes of intercellular mitochondrial transfer. Exposure to stress signals (e.g., dysfunctional mitochondria, mitoDAMPs, and NAD⁺) triggers the transfer of healthy mitochondria from donor cells to stressed/injured recipient cells via the activation of distinct signaling pathways and different routes, such as TNTs (1), EVs (2), and GJs (3). Key participants in the development of TNTs are F-Actin, microtubule, and intermediate filaments. Microtubule-based mitochondrial movement is mediated by Miro/TRAK complex attached to KIF5 kinesin/dynein molecular motors, whereas myosin motors are involved in mitochondrial transport based on actin. The NAD⁺/CD38/cADPR/Ca²⁺ pathway is involved in the release of EVs. In the presence of NAD⁺, CD38 can synthetize cADPR through its cyclase activity. As second messenger, cADPR triggers the release of the intracellular Ca²⁺ from the Endoplasmic reticulum by acting on Ryanodine Receptor (RyR). Therefore, the calcium-mediated activation of exocyst complex leads to the release of vesicles into the extracellular space. Importantly, the endocytosis of EVs may also occur via these mechanisms. Cx43-GJs are often located to one end of specific TNTs and the transcellular transfer of mitochondria may occur via gap junction internalization

Fig. 2

Current model of TNTs formation via Eps8-IRSp53 interaction. In the cellular environment, the assembly of actin can be organized into two general types of architectures in balance with each other, such as branched actin networks and closely packed parallel arrays. The inhibition of Arp2/3-dependent branched filaments enhances the synergic activity of Eps8-IRSp53 complex at the membrane causing the shift of the actin balance in favour of polymerization of long, linear filaments for TNTs outgrowth. In this context, Eps8 seems to play a crucial role, possibly through renewed interactions with proteins and signaling pathways involved in actin dynamics, including phospho-regulators of cofilin (e.g., slingshot protein phosphatases and LIM-kinases), and coronins (e.g., Coro2b). Therefore, changes in Eps8’s interactome would lead to drastic reduction of actin filament turnover and disassembly of Arp2/3 networks, while promoting the extension and organization of actin