Mitochondria are the tiny cellular energy factories, fuelled by fats and sugars, which produce the ATP that powers most life on our planet. And when animals' metabolic demands increase, their mitochondrial levels rise to satisfy their increasing ATP demands. Chris Moyes, from Queen's University,Canada, explains that the key molecular components that control mitochondrial levels in mammals are well understood, but how mitochondrial proliferation is regulated in lower vertebrates was less clear. According to Moyes, the PPAR gamma coactivator (PGC-1) family of proteins are the `master regulators' of mitochondrial synthesis in mammals. They work in conjunction with other transcription factors, such as NRF-1 to control mitochondrial gene expression,and PPAR to regulate the mitochondrion's fuel choice. Teaming up with Christophe LeMoine and Christine Genge, Moyes decided to find out whether PGC-1α and PGC1-β are also key players in the metabolic remodelling of a more `comparative' model; the goldfish(p. 1448). According to Moyes, fish respond to cold in the same way that animals respond to endurance training; their mitochondrial levels rise. So if he wanted to identify key cellular factors involved in mitochondrial proliferation during metabolic remodelling, all he'd have to do was maintain fish at different temperatures for several weeks as they adjusted their mitochondrial levels,and track the expression of remodelling related genes to identify the key transcriptional regulator. The goldfish was the obvious candidate, surviving temperatures that other model species can't tolerate.
Having kept the fish at 4, 20 and 35°C for 3 weeks, the team collected heart, muscle and liver samples and measured the mRNA levels of PGC-1α,PGC-1β, and the PPAR and NRF-1 transcription factors; key factors known to be involved in mammalian mitochondrial synthesis. LeMoine and Genge also measured the mRNA and enzyme activity levels of three major mitochondrial metabolic proteins (citrate synthase and two cytochrome oxidase subunits I and IV), to see if they correlated with PGC-1 expression levels.
But the team was in for a surprise. PGC-1α levels did not rise as mitochondrial gene expression increased in response to the cold; they plummeted. And when the team compared both PGC-1 transcript levels with the expression of mitochondrial genes and NRF-1 they found that PGC-1β was the protein regulating mitochondrial synthesis. So PGC-1β, and not PGC-1α, is the master regulator of mitochondrial synthesis in goldfish.
Knowing that animals also remodel mitochondria depending on which fuel they consume, the team fed fish on high fat, low fat and restricted diets to see how PGC1 regulated mitochondrial gene expression. This time PGC1α levels rose in line with the PPAR transcription factor, which regulates fat metabolism, suggesting that PGC1α has a role in setting the mitochondria's fuel preference.
So, unlike mammals, where metabolic remodelling is controlled by the PGC-1α master regulator, fish have opted for a division of labour scheme, with individual PGC-1 proteins responsible for different aspects of the remodelling response to altered metabolic demands.
