MFSD7C switches mitochondrial ATP synthesis to thermogenesis in response to heme

Yingzhong Li,Amanda Del Rosario,Nikola A Ivica,Matthew G Vander Heiden,Guangan Hu,Dimitrios P Papageorgiou,Douglas R Brown,Paula T Hammond,Walter W Chen,Lucas B Sullivan,Ting Dong,Yanpu He,Marianna Kleyman,Jianzhu Chen

doi:10.1038/s41467-020-18607-1

Abstract

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.

Highlights

ATP synthesis and thermogenesis are two critical outputs of mitochondrial respiration
We show: (i) major facilitator superfamily domain containing 7C (MFSD7C) resides in the mitochondria and interacts with components of electron transport chain (ETC) complexes and sarcoendoplasmic reticulum Ca2+-ATPase 2b (SERCA2b). (ii) Knockout of Mfsd7c results in uncoupled mitochondrial respiration, characterized by increased oxygen consumption rate (OCR) and thermogenesis, a phenotype that is phenocopied by treating parental cells with heme. (iii) The knockout phenotype is corrected by expression of both a full-length and an N-terminal domain (NTD)-truncated MFSD7C, but only the former corrects response to heme. (iv) Mechanistically, binding of heme to the NTD dissociates MFSD7C from ETC components and SERCA2b, leading to SERCA2b stabilization and increased thermogenesis
We identify MFSD7C as a heme-regulated switch that controls the coupling of mitochondrial respiration

Summary

Introduction

ATP synthesis and thermogenesis are two critical outputs of mitochondrial respiration. SERCA2b was shown to be required for thermogenesis in beige adipocytes of Ucp1−/− mice and in pigs[10], which lack a functional copy of Ucp[1], while SERCA1 may stimulate thermogenic activity in white adipocytes in mice[11] Despite these findings, molecular mechanisms that govern whether the energy stored in the mitochondrial proton gradient is used for ATP synthesis or thermogenesis to meet dynamic cellular requirements are largely unknown. Relevant to energy metabolism, heme is a co-factor for several electron transport chain (ETC) components, where it mediates electron transfer reactions that are coupled to formation of the mitochondrial proton gradient[14] These observations highlight the critical function of heme in energy metabolism, but whether it plays any role in regulating mitochondrial respiration has not been examined. Our study identifies that MFSD7C switches ATP synthesis to thermogenesis in response to heme, linking the outputs of mitochondrial respiration to the cell’s metabolic state and nutrient supply

Methods

Results

Conclusion