Updated project metadata. The metabolic plasticity of mitochondria supports cell development and differentiation and ensures cell survival under stress. The peptidase OMA1 regulates mitochondrial morphology and stress signaling and orchestrates tumorigenesis and cell fate decisions in a cell and tissue-specific manner. Here, we have used unbiased systemic approaches to demonstrate that OMA1-dependent cell fate decisions are under metabolic control. A metabolism-focus CRISPR screen combined with an integrated analysis of human expression data unraveled a protective role of OMA1 against DNA damage. Nucleotide deficiencies induced by chemotherapeutic agents promote the selective, p53-dependent apoptosis of cells lacking OMA1. The protective effect of OMA1 does not depend on OMA1 activation nor on OMA1-mediated OPA1 and DELE1 processing. OMA1-deficient cells have reduced glycolytic capacity and accumulate OXPHOS proteins upon DNA damage. OXPHOS inhibition restores glycolysis and confers resistance against DNA damage. Thus, metabolic cues determine cell fate decisions by OMA1, which sheds new light on the role of OMA1 in cancerogenesis.