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However, it had no beneficial effects on the survival rate of human malignant mesothelioma (<jats:styled-content style=\"fixed-case\">HMM<\/jats:styled-content>) patients. The present study was performed to elucidate the underlying mechanism of metformin resistance in <jats:styled-content style=\"fixed-case\">HMM<\/jats:styled-content> cells. Glucose\u2010starved <jats:styled-content style=\"fixed-case\">HMM<\/jats:styled-content> cells had enhanced resistance to metformin, demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria, such as decreased <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content> synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (<jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>). Intriguingly, Mdr1 was significantly upregulated in mitochondria but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with carbonyl cyanide m\u2010chlorophenyl hydrazone, an <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content> depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout <jats:styled-content style=\"fixed-case\">HMM<\/jats:styled-content> cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in <jats:styled-content style=\"fixed-case\">HMM<\/jats:styled-content> cells, which could be a potential target for improving its therapeutic efficacy.<\/jats:p>","DOI":"10.1111\/cas.13952","type":"journal-article","created":{"date-parts":[[2019,1,28]],"date-time":"2019-01-28T22:39:08Z","timestamp":1548715148000},"page":"1256-1267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1"],"prefix":"10.1111","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2413-5287","authenticated-orcid":false,"given":"Sung\u2010Hyun","family":"Hwang","sequence":"first","affiliation":[{"name":"Laboratory of Veterinary Clinical Pathology College of Veterinary Medicine Seoul National University  Seoul 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