Mitochondrial DNA (mtDNA) mutations increase the risk of health issues with overlapping clinical phenotypes. We propose that patient-derived induced pluripotent stem cells (iPSCs) can serve as surrogates for studying mitochondrial diseases, provided a standardized protocol is used to mitigate effects of mtDNA heteroplasmy. Accordingly, we reprogrammed peripheral blood mononuclear cells (CytoTune Kit) from mtDNA disease patients with epilepsy enrolled in clinical trials. After culturing the reprogrammed cells, six iPSC cell colonies were selected (Alkaline Phosphatase Live Stain) from each donor, pooled, and sorted by SSEA4+ marker at passage 6. Pluripotency was confirmed using OCT4 immuno-staining and RT-PCR for OCT4, NANOG, and SOX2 at passage 10. Because two of the patients (m.3243A>G MT-TL1, MELAS, and m.T8993G MT-ATP6, Leigh Syndrome) showed signs of improvement on drug therapy, we differentiated their iPSCs into cardiomyocytes (iCMs) and characterized them using immuno-staining (cTnT). We then screened the substrate utilization preferences of the iCMs using Phenotype MicroArray Mammalian assays (Biolog). The MELAS-iCMs failed to metabolize lactic acid, L-ornithine, and branched-chain amino acids, but performed better than control iCMs in the presence of arginine and glycerol phosphate. In contrast, LS-iCMs exhibited distinctly different substrate preferences and thrived in the presence of acetoacetic acid and α-keto-butyric acid with reduced oxidative stress (AmplexRed). The failure of MELAS-iCMs to survive in the presence of only lactic acid recapitulates a characteristic feature of MELAS, underscoring the potential of iPSCs for disease modeling. Our findings suggest that diverse outcomes to nutritional and pharmaceutical interventions must be tailored to each patient. To validate the pharmacological efficacy of iCMs, we will continuously evaluate their response in patients who are refractory to treatment.