Related Experiment Video
Updated: Jul 9, 2026
10:31
A Model Membrane Platform for Reconstituting Mitochondrial Membrane Dynamics
Published on: September 2, 2020
Metalloprotease-mediated OPA1 processing is modulated by the mitochondrial membrane potential
Olwenn Guillery1, Florence Malka, Thomas Landes
1Inserm U582, 75651 Paris cedex 13, France.
Biology of the Cell
|December 14, 2007
Summary
Mitochondrial OPA1 processing into short isoforms is regulated by inner membrane potential and mediated by the YME1L metalloprotease, impacting mitochondrial dynamics but not apoptosis.
Area of Science:
- Mitochondrial biology
- Protein processing
- Cellular dynamics
Background:
- Optic atrophy type 1 (OPA1) is a mitochondrial intermembrane space protein crucial for membrane fusion.
- OPA1 exists in multiple isoforms generated by alternative splicing and proteolytic processing, similar to its yeast counterpart Mgm1p.
- This study investigates the specific mechanisms and regulators of OPA1 proteolytic processing.
Purpose of the Study:
- To identify the proteases responsible for OPA1 processing.
- To determine the cellular conditions that regulate OPA1 processing.
- To elucidate the functional consequences of OPA1 processing on mitochondrial dynamics and apoptosis.
Main Methods:
- Analysis of OPA1 isoform patterns in various mammalian cell types.
- Investigation of OPA1 processing kinetics under conditions of altered mitochondrial membrane potential, oxidative phosphorylation, and glycolysis.
- Inhibition studies using heavy-metal chelators and genetic manipulation (knock-down, mutations) of candidate proteases (PARL, paraplegin, YME1L).
- Assessment of OPA1 interactions with mitofusins (Mfn1, Mfn2) and effects of OPA1 processing on apoptotic release of OPA1 and cytochrome c.
Main Results:
- Mammalian cells exhibit distinct long (L-OPA1) and short (S-OPA1) OPA1 isoforms.
- Loss of inner mitochondrial membrane potential triggers rapid L-OPA1 to S-OPA1 conversion.
- OPA1 processing is mediated by a metalloprotease, with YME1L identified as the likely protease, while PARL and paraplegin are not directly involved.
- OPA1 processing is stimulated during apoptosis but does not influence the release of OPA1 or cytochrome c.
- All OPA1 isoforms interact with Mfn1 and Mfn2, irrespective of membrane potential or processing state.
Conclusions:
- Metalloprotease-dependent processing of OPA1 is modulated by the mitochondrial inner membrane potential.
- The YME1L metalloprotease is the primary mediator of OPA1 processing.
- OPA1 processing is distinct from its role in apoptotic mitochondrial outer membrane permeabilization.
Related Concept Videos
01:19Translocation of Proteins into the Mitochondria
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
01:39Mitochondrial Precursor Proteins
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.
Most of the mitochondrial precursors...
Most of the mitochondrial precursors...
01:21Structure of Porins
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 precursors...
01:34Protein Transport into the Inner Mitochondrial Membrane
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.
Transport of mitochondrial precursors across the TIM23 channel is driven by...
Transport of mitochondrial precursors across the TIM23 channel is driven by...
01:39Mitochondrial Protein Sorting
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...
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
01:12Porin Insertion in the Outer Mitochondrial Membrane
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.
Three models describe the assembly of porins by the SAM complex and their insertion into the outer membrane. Model 1 suggests that porins are assembled outside the SAM channel as the...
Three models describe the assembly of porins by the SAM complex and their insertion into the outer membrane. Model 1 suggests that porins are assembled outside the SAM channel as the...