MFSD7C switches mitochondrial ATP synthesis to thermogenesis in response to heme

Nat Commun. 2020 Sep 24;11(1):4837. doi: 10.1038/s41467-020-18607-1.


ATP synthesis and thermogenesis are two critical outputs of mitochondrial respiration. How these outputs are regulated to balance the cellular requirement for energy and heat is largely unknown. Here we show that major facilitator superfamily domain containing 7C (MFSD7C) uncouples mitochondrial respiration to switch ATP synthesis to thermogenesis in response to heme. When heme levels are low, MSFD7C promotes ATP synthesis by interacting with components of the electron transport chain (ETC) complexes III, IV, and V, and destabilizing sarcoendoplasmic reticulum Ca2+-ATPase 2b (SERCA2b). Upon heme binding to the N-terminal domain, MFSD7C dissociates from ETC components and SERCA2b, resulting in SERCA2b stabilization and thermogenesis. The heme-regulated switch between ATP synthesis and thermogenesis enables cells to match outputs of mitochondrial respiration to their metabolic state and nutrient supply, and represents a cell intrinsic mechanism to regulate mitochondrial energy metabolism.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Cytochrome-c Oxidase Deficiency
  • Electron Transport Complex III
  • Electron Transport Complex IV
  • Energy Metabolism / physiology
  • Gene Knockout Techniques
  • HEK293 Cells
  • Heme / metabolism*
  • Humans
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism
  • Protein Domains
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Signal Transduction
  • THP-1 Cells
  • Thermogenesis / physiology*


  • FLVCR2 protein, human
  • Membrane Transport Proteins
  • Receptors, Virus
  • Heme
  • Adenosine Triphosphate
  • Electron Transport Complex IV
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Electron Transport Complex III
  • ATP2A2 protein, human