What is PGAM5 and Its Role in Health and Disease?

Phosphoglycerate mutase family member 5 (PGAM5) is an enzyme located within the cell’s mitochondria. This protein belongs to a larger family of enzymes known as phosphoglycerate mutases. Primarily found on the mitochondrial membranes, PGAM5 is widely distributed in tissues such as the heart, brain, and kidneys, hinting at its importance in cellular activities.

Scientists study PGAM5 for its role as a mitochondrial phosphatase, an enzyme that removes phosphate groups from other proteins. This function allows it to act as a sensor for reactive oxygen species (ROS), which are molecules that signal cellular stress. The protein exists in two forms and can assemble into different structures, which contributes to its ability to perform multiple functions within the cell.

Cellular Roles of PGAM5

PGAM5’s primary job within the cell is to act as a serine/threonine phosphatase, meaning it removes phosphate groups from specific amino acids on other proteins. This enzymatic activity is central to its function in maintaining mitochondrial health, a process known as mitochondrial quality control. By dephosphorylating target proteins, PGAM5 can alter their activity, location, or stability, influencing a range of cellular processes.

One process regulated by PGAM5 is mitochondrial dynamics, which involves the continuous fission (splitting) and fusion (joining) of mitochondria. The protein promotes mitochondrial fission by dephosphorylating Dynamin-1-like protein (Drp1). It can also encourage mitochondrial fusion by dephosphorylating and protecting Mitofusin-2 (MFN2) from degradation. This dual role allows cells to adapt their mitochondrial network structure in response to changing energy demands.

PGAM5 also participates in mitophagy, the selective removal of damaged mitochondria. It accomplishes this by dephosphorylating a protein called FUNDC1, an event that initiates the clearance of the compromised organelles. This quality control mechanism prevents the accumulation of damaged mitochondria, which could otherwise harm the cell.

PGAM5 in Cellular Signaling Pathways

The influence of PGAM5 extends beyond mitochondrial maintenance and into cellular signaling, particularly in pathways that decide a cell’s fate under stress. It acts as a checkpoint, integrating signals related to cellular damage and determining whether a cell should survive or undergo programmed cell death. This function is linked to its ability to sense mitochondrial stress and its location at the mitochondrial membranes.

A role for PGAM5 is in a form of programmed cell death called necroptosis. When a cell is under severe stress, PGAM5 can be targeted by a protein called RIPK3. This interaction helps to recruit a protein complex to the mitochondria, leading to the cell’s demise. This pathway is a defense mechanism to eliminate infected or damaged cells.

PGAM5 is also involved in other cell death pathways, such as apoptosis. During intrinsic apoptosis, PGAM5 can form a complex with proteins like Bax and Drp1. It also regulates the body’s response to oxidative stress by forming a complex with the proteins KEAP1 and NRF2. Through these interactions, PGAM5 helps to translate mitochondrial stress signals into broader cellular decisions.

Implications of PGAM5 in Health and Disease

The proper functioning of PGAM5 is important for cellular health, and its dysregulation is implicated in a variety of human diseases. Because of its role in mitochondrial quality control and cell death pathways, either too much or too little PGAM5 activity can contribute to pathology. The specific impact of PGAM5 often depends on the tissue type and the nature of the disease.

In neurodegenerative disorders like Parkinson’s disease, PGAM5’s functions are particularly relevant. The health of mitochondria is important for the survival of neurons, and failures in mitochondrial clearance and dynamics are hallmarks of Parkinson’s. PGAM5’s involvement in both mitophagy and necroptosis suggests that its malfunction could lead to the accumulation of damaged mitochondria and the death of neurons.

PGAM5’s role in cell survival and death also links it to cancer. In some cancers, such as hepatocellular carcinoma and melanoma, high levels of PGAM5 are associated with a poor prognosis, suggesting it may promote tumor cell survival. In other contexts, it can enhance the effectiveness of chemotherapy by promoting cell death. Dysregulation of PGAM5 has also been connected to metabolic disorders, inflammation, and ischemia-reperfusion injury.

Research and Therapeutic Perspectives

The growing understanding of PGAM5’s diverse roles has made it an attractive subject for research and a potential target for new therapies. Scientists use various models, including genetically modified animals and cell cultures, to investigate the mechanisms by which PGAM5 functions. These studies aim to clarify how its activity is controlled and contributes to specific disease states.

Developing drugs that can modulate PGAM5 activity is an active area of investigation. Depending on the disease, the therapeutic goal might be to either inhibit or activate the enzyme. For instance, in diseases where excessive cell death is a problem, such as in certain neurodegenerative conditions or ischemia-reperfusion injury, a PGAM5 inhibitor could be beneficial.

Conversely, in some cancers where PGAM5’s pro-survival functions are hijacked by tumor cells, an inhibitor might also be useful. Activating PGAM5 could be a strategy to enhance the clearance of damaged mitochondria in other contexts. The development of such targeted therapies faces challenges, including the need for high specificity to avoid unintended effects due to PGAM5’s multiple roles throughout the body.