Editorial to the special issue on extracellular vesicles and mitochondria in CNS function and disease

Abstract

Extracellular vesicles (EVs) have emerged as critical mediators of cell-to-cell communication. More recently, a subset of these vesicles has been found to contain mitochondria (EV-Mito). These mitochondria-bearing EVs may act as non-cell-autonomous signaling entities and serve as potential biomarkers for injury and recovery in central nervous system (CNS) pathophysiology. Mitochondria play a vital role in regulating cellular respiration, metabolism, and overall tissue function. In the context of CNS injury or disease, mitochondrial dysfunction can disrupt metabolic homeostasis, leading to cell death and inflammation. Consequently, restoring mitochondrial function represents a key therapeutic target with strong translational potential. This special issue of JCBFM presents a multidisciplinary collection of high-impact reviews and original research articles. These contributions cover a broad spectrum—from basic studies on EV-mediated mechanisms in CNS disorders and the molecular pathways underlying intercellular mitochondrial transfer, to therapeutic applications of EVs and mitochondrial transplantation in cellular and animal models. The issue also highlights the latest clinical trial developments assessing the feasibility of EV and mitochondrial transplantation in cerebral ischemia. Collectively, these articles offer valuable insights into emerging research directions and underscore the many unresolved questions that remain—particularly regarding the quantitative thresholds required for treatment efficacy and the molecular mechanisms driving beneficial tissue remodeling.

Extracellular vesicles (EVs) are small, membrane-bound particles released into the extracellular environment and play essential roles in intercellular communication in the regulation of immune system, aging, and tissue injury and repair.^1–4 EVs can be formed within cells by inward membrane budding of cell organelles including late endosomes or lysosomes (so-called exosomes, typical size 60–150 nm) or outward membrane budding of the plasma membrane (so-called ectosomes, typical size > 100 nm).^1,4 Due to their nanosize, intrinsic bioproperties, and ability to cross biological barriers, EVs serve as potential biomarkers or potent therapeutics for various central nervous system (CNS) diseases.^5–8 Under conditions of inflammation, structurally and functionally intact and damaged mitochondria and mitochondria fractions can be released by different cells packaged in EVs.^9–13 These structures can restore mitochondrial function and cell metabolism of inflamed cells (in case of functional mitochondria)^9,11 or be degraded as measure of cell protection via a process termed transcellular mitophagy (in case of damaged mitochondria).^10,12,13 During the past decade, investigations into the CNS functions of EVs including mitochondria-packaging EVs has opened a new window into our mechanistic understanding of the neurological disorders of the brain, and the field is rapidly evolving in direction of clinical translation. However, much still remains to be deciphered and explained.

This special issue features a series of invited review and original research articles that explore the fundamental mechanisms of EVs and mitochondria-mediated plasticity under pathophysiological conditions, along with their clinical implications (Table 1). Hermann et al. ¹⁴ highlights the interaction sites of EV communication and how these EVs take part in stabilizing cell metabolism, immune response, neuronal plasticity, and then functional neurological recovery in the context of restoring mitochondrial function after brain injury along with overviewing the potential of clinical translation of EV-based therapies. Moreover, Zhou et al. ¹⁵ discusses components inside EVs and further engineering to target EV delivery to specific cell types along with the context of diseases. Notably, Miyauchi et al. ¹⁶ implicates the therapeutic potential of platelet-rich plasma (PRP)-derived EVs in stroke. Especially, exercise-trained donor PRP-derived EVs enhance neuroregeneration along with improving neurological function in a mouse model of stroke, offering a technical framework to address ongoing inquiries into where and how therapeutic EVs are obtained and prepared for administration.

Table 1.

Contents in special issue extracellular vesicles and mitochondria in CNS function and disease.

Review articles	Authors
Mitochondria transfer for myelin repair	Pluchino et al.
Engineering small extracellular vesicles: unlocking the brain’s secret passage for central nervous system therapies	Li et al.
Regulation of synaptic mitochondria by extracellular vesicles and its implications for neuronal metabolism and synaptic plasticity	Zeng et al.
The age-associated decline in neuroplasticity and its implications for post-stroke recovery in animal models of cerebral ischemia: the therapeutic role of extracellular vesicles	Popa-Wagner et al.
Molecular and cellular mechanisms of mitochondria transfer in models of central nervous system disease	Nakano et al.
Extracellular vesicles lay the ground for neuronal plasticity by restoring mitochondrial function, cell metabolism and immune balance	Hermann et al.
Autologous mitochondrial transplant for acute cerebral ischemia: Phase 1 trial results and review	Walker et al.
Mitochondrial unfolded protein response (UPRmt) as novel therapeutic targets for neurological disorders	Chen et al.
Therapeutic and diagnostic potential of extracellular vesicle (EV)-mediated intercellular transfer of mitochondria and mitochondrial components	Wang et al.
Extracellular vesicle-mediated mitochondria delivery: premise and promise	S Manickam et al.
Extracellular vesicles and mitochondria in central nervous system diseases	Park et al.
Original articles
Upregulation of astrocytic mitochondrial functions via Korean red ginseng-induced CREB-BKα-HIF-1α axis through L-type Ca2+ channel subunits α1C and β4	Kim et al.
Exercise-induced extracellular vesicles derived from platelet-rich plasma improved recovery after ischemic stroke	Miyauchi et al.
Circulating extracellular vesicles in facilitated stroke recovery via MiR-451-5p/MIF and MiR-451-5p/CCND1 axes	Hira et al.
Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging	Gopal et al.
Therapeutic mitochondria treatment amplifies macrophage-mediated phagocytosis and recycling exocytosis	Tanaka et al.
Deactivation of ceramide de novo synthesis induces cerebral angiogenesis and microvascular remodeling post-ischemia/reperfusion in mice via mechanisms not predominated by extracellular vesicles	Mohamud Yusuf et al.
Rapid communication
Periprocedural therapeutics do not impair extracellular mitochondrial viability in transplantation	Miralles et al.

Mitochondria are energetic components of cells and essential for maintaining cellular function in mammals ¹⁷ through regulating levels of adenosine triphosphate, ¹⁸ fatty acids, ¹⁹ and cellular calcium. ²⁰ In a context of CNS disease, accumulating mitochondrial ROS and inflammasome along with imbalanced mitochondrial membrane permeability may cause progression of cell death and neuroinflammation. ²¹ Besides these deleterious pathways, mitochondria are known to detect stress signals including damage and accumulation of toxic proteins then counteract them via, so called, mitochondrial unfolded protein response for maintaining intracellular homeostasis. This pathway includes mitophagy, mitochondrial biogenesis, and metabolic adaptations and are overviewed by Chen et al. ²² in this special issue.

More recently, emerging data suggest that mitochondria encapsulated within EVs may be released into extracellular space, potentially transferred from cell to cell and directly participate in non-cell autonomous mechanisms in CNS.^11,23 The original article from Velmurugan et al. ²⁴ represents endogenous intercellular mitochondria transfer in the brain wherein astrocytes delivered their mitochondria to adjacent brain endothelial cells and pericytes through EV loaded with mitochondria (EV-Mito) assessed by 3D reconstruction z-stack images in astrocytic mitochondrial Dendra2 transgenic mice. Given that endogenous mitochondria transfer may support metabolic homeostasis in cells, exogenous mitochondria transplantation therapy is rapidly emerged as a new therapeutic intervention to promote gray and white matter recovery in CNS disorders summarized in review articles.^25,26 Nakano et al. ²⁶ added an overview of experimental methodologies including tissue sourcing, mitochondria isolation, storage, and modification for efficient delivery and Manickam et al. ²⁷ further discussed delivery of EV-enclosed mitochondria produced in cells. In this context, Tanaka et al. ²⁸ developed a method to encapsulate mRNAs carried by mitochondria in lipid nanoparticles, generating EV-Mito mRNAs that amplified macrophage-mediated phagocytosis and recycling exocytosis, filling a gap-of-knowledge on feasibility of delivery of mitochondrial components to cells together with partly addressing how administered mitochondria influence macrophage-mediated innate immune response. Notably, the latest update of human clinical trials conducted by Walker et al. ²⁹ which draws attention to essential issues such as limited tissue samples and constrained time for isolation followed by transplantation in the acute clinical setting of mitochondria administration therapy.

Altogether, this special issue presents a multidisciplinary collection of high-impact review articles and original research spanning a broad spectrum—from fundamental studies on EV and mitochondrial mechanisms in CNS diseases, to molecular pathways involved in intercellular mitochondrial transfer, and therapeutic applications of EVs and mitochondrial transplantation in both cellular and animal models. It also includes the latest developments from human clinical trials. Future research exploring molecular mechanisms, quantitative thresholds, quality control, and the roles of various EV and EV-mitochondria components may pave the way for novel strategies to enhance brain functional recovery and advance clinical translation in CNS disorders.