Mitochondrial Transfer in the Neurovascular Unit, Not Only for Energy Rescue: A Systematic Review

Abstract

Despite substantial evidence highlighting molecular communication within the components of neurovascular units (NVU), the interactions at the organelle level have been insufficiently explored in recent decades. Mitochondria, for instance, beyond their traditional role as energy supply for intracellular metabolism and survival, provide a novel perspective on intercellular connections through mitochondrial transfer. These transferred mitochondria not only carry bioactive molecules but also signal to mitigate risks in both healthy and pathological conditions. In this review, we summarized mitochondrial transfer events, relevant routes, and underlying molecular mechanisms originating from diverse cell populations within NVU. We particularly focus on the therapeutic potential of this mechanism in treating central nervous system disorders, notably neurodegenerative diseases marked by mitochondrial dysfunction and then highlight the promising prospects of exogenous mitochondrial supplementation as a treatment target.

Figure 1.

An overview of mitochondrial transfer in the NVU. Astrocytes serve as the center of mitochondrial delivery. (A) Mitochondria move in the TNT between pericytes, but do not enter the cell on the other side. (B) Astrocytes clear injured mitochondria from axons. (C) Microglia release dysfunctional mitochondria into the extracellular environment (for example, by exocytosis).

Figure 2.

The mechanism of mitochondrial transfer via TNTs. After stresses such as ischemia, hypoxia and amyloid beta, the TNT initiates the process from the cell membrane via the Akt/PI3K/mTOR pathway. In the stressed cell, the difference in S100A4 concentration that is reduced by upregulated caspase-3 provides the TNT with a direction for targeting cells. During the extension of unfinished TNT, βCaMKII phosphorylated by Wnt5a separates from actins, which allows for the aggregation of actins and the formation of the skeleton. The partial enlarged view shows the detailed structure that helps mitochondria move in the TNT.

Figure 3.

The mechanism of mitochondrial transfer via MVs. Increased transmembrane CD38 turns NAD into cADPR. Together they improve transferred mitochondrial quality by O-GlcNAcylation. Intracellular calcium ions that are elevated due to cADPR may attract the aforesaid mitochondria to the cell membrane. Excessive ATP freed from circumambient cells results in the abscission of vesicles containing mitochondria. Finally, these vesicles merge with target cells according to integrin-associated signals.