Structural Mechanism of Transport of Mitochondrial Carriers

Annu Rev Biochem. 2021 Jun 20:90:535-558. doi: 10.1146/annurev-biochem-072820-020508. Epub 2021 Feb 8.

Abstract

Members of the mitochondrial carrier family [solute carrier family 25 (SLC25)] transport nucleotides, amino acids, carboxylic acids, fatty acids, inorganic ions, and vitamins across the mitochondrial inner membrane. They are important for many cellular processes, such as oxidative phosphorylation of lipids and sugars, amino acid metabolism, macromolecular synthesis, ion homeostasis, cellular regulation, and differentiation. Here, we describe the functional elements of the transport mechanism of mitochondrial carriers, consisting of one central substrate-binding site and two gates with salt-bridge networks on either side of the carrier. Binding of the substrate during import causes three gate elements to rotate inward, forming the cytoplasmic network and closing access to the substrate-binding site from the intermembrane space. Simultaneously, three core elements rock outward, disrupting the matrix network and opening the substrate-binding site to the matrix side of the membrane. During export, substrate binding triggers conformational changes involving the same elements but operating in reverse.

Keywords: ADP/ATP carrier; bioenergetics; membrane protein dynamics; mitochondrial diseases; mitochondrial physiology; uncoupling protein.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aggrecans / chemistry
  • Aggrecans / genetics
  • Aggrecans / metabolism
  • Amino Acid Sequence
  • Amino Acids / chemistry
  • Amino Acids / metabolism
  • Binding Sites
  • Biological Transport
  • Calcium / metabolism
  • Cardiolipins / metabolism
  • Conserved Sequence
  • Cytoplasm / metabolism
  • Humans
  • Mitochondrial ADP, ATP Translocases / chemistry
  • Mitochondrial ADP, ATP Translocases / metabolism
  • Mitochondrial Membrane Transport Proteins / chemistry*
  • Mitochondrial Membrane Transport Proteins / genetics*
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mutation
  • Protein Conformation
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism

Substances

  • ACAN protein, human
  • Aac3 protein, S cerevisiae
  • Aggrecans
  • Amino Acids
  • Cardiolipins
  • Mitochondrial Membrane Transport Proteins
  • PET9 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Mitochondrial ADP, ATP Translocases
  • Calcium