Therapies targeting epigenetic changes for cancer treatment are in Phase I/II trials; however, all of these target only nuclear DNA. Emerging evidence suggests presence of methylation marks on mitochondrial DNA (mtDNA); but their contribution in cancer is unidentified. Expression of genes encoded on mtDNA are altered in cancer cells, along with increased glycolytic flux. Such glycolytic flux and elevated reactive oxygen species is supported by increased antioxidant; glutathione. MicroRNA-34a can translocate to mitochondria, mediate downstream apoptotic effects of tumor suppressor P53, and inhibit the antioxidant response element Nrf-2, resulting in depleted glutathione levels. Based on such strong rationale, we encapsulated microRNA-34a in our well-established Hyaluronic-Acid nanoparticles and delivered to cisplatin-sensitive and cisplatin-resistant A549-lung adenocarcinoma cells. Successful delivery and uptake in cells resulted in altered ATP levels, decreased glycolytic flux, Nrf-2 and glutathione levels, ultimately resulting in caspase-3 activation and apoptosis. Most important were the concurrent underlying molecular changes in epigenetic status of D-loop on the mtDNA and transcription of mtDNA-encoded genes. Although preliminary, we provide a novel therapeutic approach in form of altered mitochondrial bioenergetics and redox status of cancer cells with underlying changes in epigenetic status of mtDNA that can subsequently results in induction of cancer cell apoptosis.