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Rewiring of energy metabolism and adaptation of mitochondrial respiratory functions are considered to impact on prostate cancer development and progression. High-resolution respirometry of paired benign and malignant human prostate tissue samples revealed reduced respiratory capacities with NADH-pathway substrates glutamate and malate in malignant tissue and a significant metabolic shift towards respiratory capacity with succinate, particularly in high-grade tumors. The load of potentially deleterious mitochondrial-DNA mutations was higher in tumor tissue and associated with unfavorable risk factors. High levels of potentially deleterious mutations in mitochondrial Complex I-encoding genes were associated with a 70% reduction in NADH-pathway capacity and compensation by increased S-pathway capacity. Structural analyses of these mutations revealed amino acid alterations leading to potentially deleterious effects on Complex I, supporting a causal relationship. RNA-seq revealed a signature of metabolic enzymes corresponding to the altered mitochondrial respiratory pathways and enabled extraction of a metagene set for prediction of shorter disease-free survival.