PGC-1α

Key takeaways

PGC-1α belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect PGC-1α to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of PGC-1α from memory before moving on to harder problems.

Reference excerpt

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1A gene. PPARGC1A is also known as human accelerated region 20 (HAR20). It may, therefore, have played a key role in differentiating humans from apes. PGC-1α is the master regulator of mitochondrial biogenesis. PGC-1α is also the primary regulator of liver gluconeogenesis, inducing increased gene expression for gluconeogenesis.

Function PGC-1α is a gene that contains two promoters, and has 4 alternative splicings. PGC-1α is a transcriptional coactivator that regulates the genes involved in energy metabolism. It is the master regulator of mitochondrial biogenesis. This protein interacts with the nuclear receptor PPAR-γ, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activity of, cAMP response element-binding protein (CREB) and nuclear respiratory factors (NRFs) . PGC-1α provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor causing slow-twitch rather than fast-twitch muscle fiber types. Endurance exercise has been shown to activate the PGC-1α gene in human skeletal muscle. Exercise-induced PGC-1α in skeletal muscle increases autophagy and unfolded protein response. PGC-1α protein may also be involved in controlling blood pressure, regulating cellular cholesterol homeostasis, and the development of obesity.

Regulation PGC-1α is thought to be a master integrator of external signals. It is known to be activated by a host of factors, including:

Reactive oxygen species and reactive nitrogen species, both formed endogenously in the cell as by-products of metabolism but upregulated during times of cellular stress. Fasting can also increase gluconeogenic gene expression, including hepatic PGC-1α. It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis. It is induced by endurance exercise and recent research has shown that PGC-1α determines lactate metabolism, thus preventing high lactate levels in endurance athletes and making lactate as an energy source more efficient. cAMP response element-binding (CREB) proteins, activated by an increase in cAMP following external cellular signals. Protein kinase B (Akt) is thought to downregulate PGC-1α, but upregulate its downstream effectors, NRF1 and NRF2. Akt itself is activated by PIP3, often upregulated by PI3K after G protein signals. The Akt family is also known to activate pro-survival signals as well as metabolic activation. SIRT1 binds and activates PGC-1α through deacetylation inducing gluconeogenesis without affecting mitochondrial biogenesis. PGC-1α has been shown to exert positive feedback circuits on some of its upstream regulators:

PGC-1α increases Akt (PKB) and Phospho-Akt (Ser 473 and Thr 308) levels in muscle. PGC-1α leads to calcineurin activation. Akt and calcineurin are both activators of NF-kappa-B (p65). Through their activation, PGC-1α seems to activate NF-kappa-B. Increased activity of NF-kappa-B in muscle has recently been demonstrated following induction of PGC-1α. The finding seems to be controversial. Other groups found that PGC-1s inhibit NF-kappa-B activity. The effect was demonstrated for PGC-1 alpha and beta. PGC-1α has also been shown to drive NAD biosynthesis to play a large role in renal protection in acute kidney injury.

Clinical significance PPARGC1A has been implicated as a potential therapy for Parkinson's disease conferring protective effects on mitochondrial metabolism. Moreover, brain-specific isoforms of PGC-1alpha have recently been identified which are likely to play a role in other neurodegenerative disorders such as Huntington's disease and amyotrophic lateral sclerosis. Massage therapy appears to increase the amount of PGC-1α, which leads to the production of new mitochondria. PGC-1α and beta has furthermore been implicated in polarization to anti-inflammatory M2 macrophages by interaction with PPAR-γ with upstream activation of STAT6. An independent study confirmed the effect of PGC-1 on polarisation of macrophages towards M2 via STAT6/PPAR gamma and furthermore demonstrated that PGC-1 inhibits proinflammatory cytokine production. PGC-1α has been recently proposed to be responsible for β-aminoisobutyric acid secretion by exercising muscles. The effect of β-aminoisobutyric acid in white fat includes the activation of thermogenic genes that prompt the browning of white adipose tissue and the consequent increase of background metabolism. Hence, the β-aminoisobutyric acid could act as a messenger molecule of PGC-1α and explain the effects of PGC-1α increase in other tissues such as white fat. PGC-1α increases BNP expression by coactivating Estrogen-related receptor alpha (ERRα) and / or AP1. Subsequently, BNP induces a chemokine cocktail in muscle fibers and activates macrophages in a local paracrine manner, which can then contribute to enhancing the repair and regeneration potential of trained muscles. Most studies reporting effects of PGC-1α on physiological functions have used mouse models in which the PGC-1α gene is either knocked out or overexpressed from conception. However, some of the proposed effects of PGC-1α have been questioned by studies using inducible knockout technology to remove the PGC-1α gene only in adult mice. For example, two independent studies have shown that adult expression of PGC-1α is not required for improved mitochondrial function after exercise training. This suggests that some of the reported effects of PGC-1α are likely to occur only in the developmental stage. In the metabolic disorder of combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 deficiency, there is a massively increased expression of PGC-1α, which is consistent with upregulated beta oxidation.

Interactions PPARGC1A has been shown to interact with:

CREB-binding protein Estrogen-related receptor alpha (ERRα), estrogen-related receptor beta (ERR-β), estrogen-related receptor gamma (ERR-γ). Farnesoid X receptor FBXW7 MED1, MED12, MED14, MED17, NRF1 Peroxisome proliferator-activated receptor gamma Retinoid X receptor alpha Thyroid hormone receptor beta ERRα and PGC-1α are coactivators of both glucokinase (GK) and SIRT3, binding to an ERRE element in the GK and SIRT3 promoters.

See also MB-3 (drug) PPARGC1B Transcription coregulator

References

Illustrations

Worked examples

Example 1 — a first encounter with PGC-1α

Start with the simplest possible case. Write down what PGC-1α claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to PGC-1α before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about PGC-1α ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of PGC-1α

In research: PGC-1α appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses PGC-1α in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: PGC-1α is common in secondary-school and first-year university syllabi. It links to neighbouring topics Exercise biochemistry, Genes on human chromosome 4, so understanding it makes those chapters shorter.
In everyday life: Look for PGC-1α outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study PGC-1α in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what PGC-1α means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain PGC-1α out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is PGC-1α in simple terms?

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1A gene. PPARGC1A is also known as human accelerated region 20 (HAR20).

Why does PGC-1α matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study PGC-1α?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on PGC-1α.