Current progress of mitochondrial transplantation that promotes neuronal regeneration

Abstract

Background: Mitochondria are the major source of intracellular adenosine triphosphate (ATP) and play an essential role in a plethora of physiological functions, including the regulation of metabolism and the maintenance of cellular homeostasis. Mutations of mitochondrial DNA, proteins and impaired mitochondrial function have been implicated in the neurodegenerative diseases, stroke and injury of the central nervous system (CNS). The dynamic feature of mitochondrial fusion, fission, trafficking and turnover have also been documented in these diseases.

Perspectives: A major bottleneck of traditional approach to correct mitochondria-related disorders is the difficulty of drugs or gene targeting agents to arrive at specific sub-compartments of mitochondria. Moreover, the diverse nature of mitochondrial mutations among patients makes it impossible to develop one drug for one disease. To this end, mitochondrial transplantation presents a new paradigm of therapeutic intervention that benefits neuronal survival and regeneration for neurodegenerative diseases, stroke, and CNS injury. Supplement of healthy mitochondria to damaged neurons has been reported to promote neuronal viability, activity and neurite re-growth. In this review, we provide an overview of the recent advance and development on mitochondrial therapy.

Conclusion: Key parameters for the success of mitochondrial transplantation depend on the source and quality of isolated mitochondria, delivery protocol, and cellular uptake of supplemented mitochondria. To expedite clinical application of the mitochondrial transplantation, current isolation protocol needs optimization to obtain high percentage of functional mitochondria, isolated mitochondria may be packaged by biomaterials for successful delivery to brain allowing for efficient neuronal uptake.

Keywords: Mitochondrial dynamics; Mitochondrial therapy; Neurodegenerative diseases; Neuronal regeneration; Stroke.

Fig. 1

Injury-induced morphogenesis and distribution of mitochondria in neurons. a Healthy neurons. b (upper panel) In response to neuronal injury, the size and number of mitochondria are increased around the axon hillock. (bottom panel) Stimuli, such as low-dose ionizing radiation stress, induces mitochondrial fusion [56]. c During neuronal regeneration, density of mitochondria and their transport are increased in the regenerating axon. Moreover, knockout of Snph or overexpressing Armcx1 have been shown to improve mitochondrial motility and promote axonal regeneration [59, 60]

Fig. 2

Mechanisms underlying mitochondria internalization. Three uptake routes for mitochondrial therapy: a Mitochondria-containing vesicles are released from healthy neurons (or donor cells) and then internalized into injured neurons. b Healthy mitochondria are transported via the actin-based tunneling nanotubes between donor cells and injured neurons. c Extracellular healthy mitochondria through focal administration are internalized into injured neuron