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Related Concept Videos

Mitochondrial Protein Sorting01:39

Mitochondrial Protein Sorting

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Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death.  Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
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Porin Insertion in the Outer Mitochondrial Membrane01:12

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Porins are beta-barrel proteins translocated to the mitochondrial outer membrane through the TOM complex into the intermembrane space. Porin precursors bind TIM chaperones within the intermembrane space and are guided to the Sorting and Assembly Machinery complex or SAM complex on the outer mitochondrial membrane.
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Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
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Structure of Porins01:21

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Mitochondria, chloroplasts, and gram-negative bacteria have transmembrane, beta-barrel proteins called porins to mediate the free diffusion of ions and metabolites across the membrane. Mitochondrial porin precursors contain conserved amino acid sequences called beta signals at their C-terminal. Beta signals have a  motif of PoXGXXHyXHy (Po-Polar, X-Any amino acid, G-Glycine, Hy-LargeHydrophobic), which are crucial for precursor recognition to initiate precursor assembly. Beta-barrel...
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Protein Transport into the Inner Mitochondrial Membrane01:34

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Nuclear encoded mitochondrial precursors are imported to the inner membrane in a multistep process involving two separate translocons, TIM22 and TIM23. TIM23 is a cation-selective pore that remains closed by the N terminal segment of the protein. Negative charges on the TIM23 act as a receptor for the incoming precursor, pulling the positively charged matrix-targeting sequence for peptide insertion and translocation.
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Mitochondrial Precursor Proteins01:39

Mitochondrial Precursor Proteins

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Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70  chaperones are targetted to TOM20-TOM22 receptor complexes.
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Measurement of Protein Import Capacity of Skeletal Muscle Mitochondria
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A protein quality control pathway at the mitochondrial outer membrane.

Meredith B Metzger1, Jessica L Scales1, Mitchell F Dunklebarger1

  • 1Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, United States.

Elife
|March 3, 2020
PubMed
Summary

Mitochondria quality control pathways for misfolded proteins are poorly understood. This study identifies novel pathways involving specific ubiquitin ligases and chaperones for degrading misfolded mitochondrial outer membrane proteins.

Keywords:
MADS. cerevisiaeUPScell biologymisfoldedquality controlyeast

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Protein Quality Control

Background:

  • Mitochondrial function relies on efficient quality control (QC) to remove misfolded proteins.
  • Existing QC pathways for mitochondrial proteins are not well-defined.
  • Novel substrates and mechanisms are needed to study mitochondrial protein degradation.

Purpose of the Study:

  • To establish and characterize novel quality control pathways for misfolded proteins on the mitochondrial outer membrane (MOM).
  • To identify the specific ubiquitin ligases, chaperones, and protein degradation machinery involved.
  • To elucidate the unique features of this mitochondrial quality control pathway.

Main Methods:

  • Utilized temperature-sensitive (ts-) mutants of peripheral MOM proteins (sen2-1HAts and sam35-2HAts) in Saccharomyces cerevisiae.
  • Investigated protein degradation using the ubiquitin-proteasome system.
  • Assessed the roles of specific ubiquitin ligases (Ubr1, San1), chaperones (Hsp70s, Sis1), and the Cdc48 complex (Cdc48-Npl4-Ufd1, Doa1, Ubx2).

Main Results:

  • Established ts- sen2-1HAts and sam35-2HAts as model substrates for MOM protein degradation.
  • Demonstrated degradation via the ubiquitin-proteasome system, with Ubr1 and San1 as key ubiquitin ligases.
  • Showed requirement for Hsp70s, Sis1, Cdc48 complex, Doa1, and Ubx2 in mitochondria-associated degradation (MAD).

Conclusions:

  • Identified a novel mitochondrial quality control pathway for peripheral MOM proteins.
  • Revealed the involvement of specific ubiquitin ligases and a unique combination of cytosolic and mitochondrial factors.
  • This pathway represents a distinct mechanism compared to other known cellular QC pathways.