Functional and regulatory profiling of energy metabolism in fission yeast

Background: The control of energy metabolism is fundamental for cell growth and function and anomalies in it
are implicated in complex diseases and ageing. Metabolism in yeast cells can be manipulated by supplying
different carbon sources: yeast grown on glucose rapidly proliferates by fermentation, analogous to tumour cells
growing by aerobic glycolysis, whereas on non-fermentable carbon sources metabolism shifts towards respiration.
Results: We screened deletion libraries of fission yeast to identify over 200 genes required for respiratory growth.
Growth media and auxotrophic mutants strongly influenced respiratory metabolism. Most genes uncovered in the
mutant screens have not been implicated in respiration in budding yeast. We applied gene-expression profiling
approaches to compare steady-state fermentative and respiratory growth and to analyse the dynamic adaptation to
respiratory growth. The transcript levels of most genes functioning in energy metabolism pathways are coherently
tuned, reflecting anticipated differences in metabolic flows between fermenting and respiring cells. We show that
acetyl-CoA synthase, rather than citrate lyase, is essential for acetyl-CoA synthesis in fission yeast. We also investigated
the transcriptional response to mitochondrial damage by genetic or chemical perturbations, defining a retrograde
response that involves the concerted regulation of distinct groups of nuclear genes that may avert harm from
mitochondrial malfunction.
Conclusions: This study provides a rich framework of the genetic and regulatory basis of energy metabolism in fission
yeast and beyond, and it pinpoints weaknesses of commonly used auxotroph mutants for investigating metabolism. As
a model for cellular energy regulation, fission yeast provides an attractive and complementary system to budding yeast.