The metabolic growth limitations of petite cells lacking the mitochondrial genome

Eukaryotic cells can survive the loss of their mitochondrial genome, but consequently suffer from severe growth defects. 'Petite yeasts', characterized by mitochondrial genome loss, are instrumental for studying mitochondrial function and physiology. However, the molecular cause of their reduced growth rate remains an open question. Here we show that petite cells suffer from an insufficient capacity to synthesize glutamate, glutamine, leucine and arginine, negatively impacting their growth. Using a combination of molecular genetics and omics approaches, we demonstrate the evolution of fast growth overcomes these amino acid deficiencies, by alleviating a perturbation in mitochondrial iron metabolism and by restoring a defect in the mitochondrial tricarboxylic acid cycle, caused by aconitase inhibition. Our results hence explain the slow growth of mitochondrial genome-deficient cells with a partial auxotrophy in four amino acids that results from distorted iron metabolism and an inhibited tricarboxylic acid cycle. Petite yeast cells lack the mitochondrial genome, which impairs growth. Vowinckel et al. identify the causes behind this growth impairment, linked to amino acid deficiencies that result from iron metabolism defects and an inhibited tricarboxylic cycle.

Automated summary

The study reveals that petite cells suffer from an insufficient capacity to synthesize glutamate, glutamine, leucine and arginine, negatively impacting their growth rate. Fast growth overcomes these amino acid deficiencies by alleviating a perturbation in mitochondrial iron metabolism and restoring a defect in the mitochondrial tricarboxylic acid cycle.