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

by Selleckchem | Jul 27 2023

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.

Comments:

The study mentioned in the background describes the role of a protein called phosphoglycerate mutase 5 (PGAM5) in sensing mitochondrial dysfunction and maintaining mitochondrial homeostasis during the regeneration process after traumatic brain injury (TBI).

The researchers observed that TBI led to increased transcription of PGAM5 during the acute phase of injury. This upregulation of PGAM5 was found to be a result of topological remodeling of a novel enhancer-promoter interaction. The elevated levels of PGAM5 correlated with the process of mitophagy, which is the selective removal of damaged mitochondria.

At a later stage of TBI, the researchers discovered that PGAM5 was cleaved by a protein called presenilins-associated rhomboid-like protein (PARL). This cleavage event resulted in increased expression of a protein called mitochondrial transcription factor A (TFAM) and enhanced mitochondrial mass. TFAM is known to play a crucial role in mitochondrial biogenesis, the process by which new mitochondria are generated within cells.

To investigate whether PGAM5 cleavage and TFAM expression were sufficient for functional recovery, the researchers used a compound called carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). FCCP is a mitochondrial oxidative phosphorylation uncoupler that reduces mitochondrial function by uncoupling the electron transport chain. They found that treatment with FCCP triggered PGAM5 cleavage, increased TFAM expression, and led to the recovery of motor function deficits in mice with controlled cortical impact (CCI), a commonly used model of TBI.

Based on their findings, the study suggests that PGAM5 may serve as a mitochondrial sensor in response to brain injury, activating its own transcription during the acute phase of injury to facilitate the removal of damaged mitochondria through mitophagy. Subsequently, PGAM5 is cleaved by PARL, resulting in increased TFAM expression and mitochondrial biogenesis at a later stage of TBI. The timely regulation of PGAM5 expression and cleavage appears to be crucial for neurite re-growth and functional recovery after TBI.