Timely expression of PGAM5 and its cleavage control mitochondrial homeostasis during neurite re-growth after
Min-Zong Liang1, Ting-Hsuan Lu2, Linyi Chen3,4
1Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.
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.
Insights
Traumatic brain injury (TBI) triggers phosphoglycerate mutase 5 (PGAM5) to sense damage and clear mitochondria. Later, PGAM5 cleavage promotes mitochondrial repair and functional recovery after brain injury.
Area of Science:
- Neuroscience
- Cell Biology
- Mitochondrial Biology
Background:
- Severe traumatic brain injury (TBI) increases the risk of neurodegenerative diseases.
- Neuronal function relies on mitochondria; injury triggers repair mechanisms.
- The specific protein sensor for mitochondrial dysfunction and regeneration pathways post-TBI remain unclear.
Purpose of the Study:
- To identify the protein sensor for mitochondrial dysfunction after TBI.
- To elucidate the mechanisms of mitochondrial homeostasis during neuronal regeneration.
- To understand the role of PGAM5 in TBI recovery.
Main Methods:
- Investigated TBI-induced changes in phosphoglycerate mutase 5 (PGAM5) transcription and cleavage.
- Analyzed the correlation between PGAM5, mitophagy, and presenilins-associated rhomboid-like protein (PARL).
- Assessed the impact of PGAM5 cleavage and mitochondrial transcription factor A (TFAM) expression on functional recovery using an uncoupler (FCCP) in a mouse model.
Main Results:
- TBI increased PGAM5 transcription via enhancer-promoter interaction, correlating with mitophagy.
- PARL-dependent PGAM5 cleavage at a later stage enhanced TFAM expression and mitochondrial mass.
- FCCP-induced PGAM5 cleavage and TFAM expression restored motor function in mice with controlled cortical impact (CCI).
Conclusions:
- PGAM5 acts as a mitochondrial sensor post-brain injury, initiating mitophagy.
- Subsequent PGAM5 cleavage by PARL promotes mitochondrial biogenesis via TFAM.
- Timely regulation of PGAM5 expression and cleavage is crucial for neuronal repair and functional recovery after TBI.
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