Rescuers from the Other Shore: Intercellular Mitochondrial Transfer and Its Implications in Central Nervous System Injury and Diseases

Abstract

As the powerhouse and core of cellular metabolism and survival, mitochondria are the essential organelle in mammalian cells and maintain cellular homeostasis by changing their content and morphology to meet demands through mitochondrial quality control. It has been observed that mitochondria can move between cells under physiological and pathophysiological conditions, which provides a novel strategy for preserving mitochondrial homeostasis and also a therapeutic target for applications in clinical settings. Therefore, in this review, we will summarize currently known mechanisms of intercellular mitochondrial transfer, including modes, triggers, and functions. Due to the highly demanded energy and indispensable intercellular linkages of the central nervous system (CNS), we highlight the mitochondrial transfer in CNS. We also discuss future application possibilities and difficulties that need to be addressed in the treatment of CNS injury and diseases. This clarification should shed light on its potential clinical applications as a promising therapeutic target in neurological diseases. Intercellular mitochondrial transfer maintains the homeostasis of central nervous system (CNS), and its alteration is related to several neurological diseases. Supplementing exogenous mitochondrial donor cells and mitochondria, or utilizing some medications to regulate the process of transfer might mitigate the disease and injury.

Keywords: Central nervous system; Intercellular mitochondrial transfer; Mitochondria; Mitochondrial quality control; Mitochondrial transplantation.

Fig. 1

Modes of intercellular mitochondrial transfer. In different ways, mitochondria are transferred between cells. A Mitochondria are transferred to recipient cells predominantly via tunneling nanotubes, a sort of membrane structure containing F-actin, microtubules, and so on. Miro1 helps mitochondria to harbor on microtubules and mitochondria are subsequently transferred horizontally. B It was also shown that mitochondria, whether encapsulated in vesicles or as free organelles, can be released into the intercellular microenvironment. These mitochondria can be directly engulfed or transferred via several receptors into recipient cells. C, D Mitochondria are also transferred by means of gap junction channels or cell fusion. Different types of cells are prone to different modes according to their characteristics and physiological states

Fig. 2

Functions of intercellular mitochondrial transfer. A Intercellular mitochondrial transfer provides a chance for cells to dispose of damaged or superfluous mitochondria by transferring them to adjacent recipient cell for degradation. B Intercellular mitochondrial transfer also transfers healthy mitochondria to recipient cells. After receiving “help-me signals” like ROS, mitochondria, and mtDNA from injured or distressed cells, the heme oxygenase-1 (HO-1)/peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) pathway of donor cells initiates mitochondrial biogenesis. Subsequently, newly generated healthy mitochondria are transferred to recipient cells. Once transferred, the separation of mitochondria occurs. Some beneficial mitochondrial parts fuse with host mitochondria, while others are degraded in lysosomes. Transferred mitochondrial also promotes endogenous mitochondrial biogenesis of recipient cells. Altogether, these changes results in improved cellular energetic metabolism. Finally, metabolic reprogramming takes place to reshape cellular phenotypes, and cell death is inhibited

Fig. 3

Potential applications of intercellular mitochondrial transfer in CNS injury and diseases. For the purpose of clinical applications, three aspects might be promising in future treatment and diagnosis in CNS injury and diseases. One of the most potential therapeutic applications is to use some strategies to modulate the transfer process to enhance efficiency. Selecting a proper cell type, like induced pluripotent stem cell (iPSCs), or using some hormones and materials such as melatonin or iron oxide nanoparticles (IONPs) are applicable ways to make this come true. Besides, due to mitochondria as rescuers, directly supplementing mitochondria, known as mitochondrial transplantation, is also an alternative therapy. Finally, as is observed that different states of mitochondria can be released into the microenvironment and circulatory system, detecting the number as well as the activity of fluid mitochondria may indicate the severity and prognosis of CNS diseases