Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance

Nat Commun. 2021 May 14;12(1):2804. doi: 10.1038/s41467-021-23071-6.


Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / pharmacology
  • Cell Line, Tumor
  • Cell Respiration / drug effects
  • Cell Respiration / physiology
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple / physiology
  • Drug Resistance, Neoplasm / physiology*
  • Female
  • HSP40 Heat-Shock Proteins / deficiency
  • HSP40 Heat-Shock Proteins / metabolism
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Oxygen Consumption / drug effects


  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • DNAJC15 protein, human
  • HSP40 Heat-Shock Proteins
  • Doxorubicin
  • Adenosine Triphosphate