Timely expression of PGAM5 and its cleavage control mitochondrial homeostasis during neurite re-growth after traumatic brain injury.

BACKGROUND: Patients suffered from severe traumatic brain injury (TBI) have twice the risk of developing into neurodegenerative diseases later in their life. Thus, early intervention is needed not only to treat TBI but also to reduce neurodegenerative diseases in the future. Physiological functions of neurons highly depend on mitochondria. Thus, when mitochondrial integrity is compromised by injury, neurons would initiate a cascade of events to maintain homeostasis of mitochondria. However, what protein senses mitochondrial dysfunction and how mitochondrial homeostasis is maintained during regeneration remains unclear. RESULTS: We found that TBI-increased transcription of a mitochondrial protein, phosphoglycerate mutase 5 (PGAM5), during acute phase was via topological remodeling of a novel enhancer-promoter interaction. This up-regulated PGAM5 correlated with mitophagy, whereas presenilins-associated rhomboid-like protein (PARL)-dependent PGAM5 cleavage at a later stage of TBI enhanced mitochondrial transcription factor A (TFAM) expression and mitochondrial mass. To test whether PGAM5 cleavage and TFAM expression were sufficient for functional recovery, mitochondrial oxidative phosphorylation uncoupler carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) was used to uncouple electron transport chain and reduce mitochondrial function. As a result, FCCP triggered PGAM5 cleavage, TFAM expression and recovery of motor function deficits of CCI mice. CONCLUSIONS: Findings from this study implicate that PGAM5 may act as a mitochondrial sensor for brain injury to activate its own transcription at acute phase, serving to remove damaged mitochondria through mitophagy. Subsequently, PGAM5 is cleaved by PARL, and TFAM expression is increased for mitochondrial biogenesis at a later stage after TBI. Taken together, this study concludes that timely regulation of PGAM5 expression and its own cleavage are required for neurite re-growth and functional recovery.

Mitochondrial Protein PGAM5 Emerges as a New Regulator in Neurological Diseases.

As mitochondrial dysfunction has increasingly been implicated in neurological diseases, much of the investigation focuses on the response of the mitochondria. It appears that mitochondria can respond to external stimuli speedy fast, in seconds. Understanding how mitochondria sense the signal and communicate with cytosolic pathways are keys to understand mitochondrial regulation in diseases or in response to trauma. It was not until recently that a novel mitochondrial protein, phosphoglycerate mutase family member 5 (PGAM5) has emerged to be a new regulator of mitochondrial homeostasis. Although controversial results reveal beneficial as well as detrimental roles of PGAM5 in cancers, these findings also suggest PGAM5 may have diverse regulation on cellular physiology. Roles of PGAM5 in neuronal tissues remain to be uncovered. This review discusses current knowledge of PGAM5 in neurological diseases and provides future perspectives.

WNT3A Promotes Neuronal Regeneration upon Traumatic Brain Injury.

The treatment of traumatic brain injury (TBI) remains a challenge due to limited knowledge about the mechanisms underlying neuronal regeneration. This current study compared the expression of WNT genes during regeneration of injured cortical neurons. Recombinant WNT3A showed positive effect in promoting neuronal regeneration via in vitro, ex vivo, and in vivo TBI models. Intranasal administration of WNT3A protein to TBI mice increased the number of NeuN+ neurons without affecting GFAP+ glial cells, compared to control mice, as well as retained motor function based on functional behavior analysis. Our findings demonstrated that WNT3A, 8A, 9B, and 10A promote regeneration of injured cortical neurons. Among these WNTs, WNT3A showed the most promising regenerative potential in vivo, ex vivo, and in vitro.

Current progress of mitochondrial transplantation that promotes neuronal regeneration.

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.

Mitochondrial therapy promotes regeneration of injured hippocampal neurons.

Due to the inhibitory microenvironment and reduced intrinsic growth capacity of neurons, neuronal regeneration of central nervous system remains challenging. Neurons are highly energy demanding and require sufficient mitochondria to support cellular activities. In response to stimuli, mitochondria undergo fusion/fission cycles to adapt to environment. It is thus logical to hypothesize that the plasticity of mitochondrial dynamics is required for neuronal regeneration. In this study, we examined the role of mitochondrial dynamics during regeneration of rat hippocampal neurons. Quantitative analysis showed that injury induced mitochondrial fission. As mitochondrial dysfunction has been implicated in neurodegenerative diseases, we tested the possibility that the mitochondrial therapy may promote neuronal regeneration. Supplying freshly isolated mitochondria to the injured hippocampal neurons not only significantly increased neurite re-growth but also restored membrane potential of injured hippocampal neurons. Together, our findings support the importance of mitochondrial dynamics during regeneration of injured hippocampal neurons and highlight the therapeutic prospect of mitochondria to the injured central nervous system.