Amazing stuff! I was previously not aware of mitochondrial fission and fusion.
Apparently, the new discoveries allow for the unification of two competing, but opposite existing models of this fission.
"Key takeaways
- Mitochondria, the tiny structures providing much of the energy that our cells need, can split apart into smaller pieces in a process called fission.
- The mechanics of mitochondrial fission have been poorly understood, holding back efforts to address serious health problems associated with defects in the process, such as cancer, cardiovascular diseases and neurodegenerative disorders.
- A pair of studies ... have revealed the molecular mechanisms behind mitochondrial fission, creating potential for future treatments.
... Less well-known are their roles in cellular signaling and in eliminating defective cells, which is important for stopping cancer before it starts.
As ... mitochondria squirm around inside cells, they split off pieces through a process called fission, and combine with each other, also known as fusion, to keep up with the cell’s complex energy demands.
Too much fission leads to many undersized mitochondria;
too much fusion leads to many oversized ones.
Imbalances between fission and fusion are associated with serious disorders of the heart, lungs and brain as well as cancer and diabetes. ...
According to the researchers, mitochondria split in a two-stage process. They found that in each phase, the same protein is used in a different way. ...
The researchers used machine learning, experiments with genetic engineering and advanced X-ray imaging, and computer models of molecular interactions. What they found melds together two leading models for explaining the mechanics of mitochondrial fission.
First, proteins from what scientists refer to as the dynamin superfamily join up to spiral around the mitochondrion like a scaffold and squeeze its elastic membrane to form a narrow neck. This process is in line with a model suggesting fission is driven by the constriction of dynamin proteins. However, constriction by itself has never been experimentally observed to induce fission.
What happens next is in line with the competing, almost opposite model, which holds that fission is driven not by the assembly (and squeezing) but rather the disassembly of the spiral scaffold into free-floating dynamin protein. The research team showed that, indeed, the floating dynamin proteins drive fission, but only when the mitochondria have been pre-squeezed into a narrow tube first. The individual free-floating proteins then flip around and use their own shape to bend the membrane inward even further by pressing against it.
In fact, at the threshold for fission, something unexpected happens: The membrane buckles suddenly and becomes so narrow that the mitochondrion can no longer remain in one piece. This snap-through instability, studied in physics and mechanical engineering, finalizes fission in a manner like an umbrella abruptly turned inside out by a wind gust. ...
Beyond the discoveries about mitochondria, this research may offer clues into the mechanisms behind other important cellular behaviors. For instance, the process by which a cell takes in a substance from the outside — vital for both communication between cells and the delivery of medicine — employs a similar change in the membrane. The process, called endocytosis, is dependent on dynamin. ..."
From the abstract (1):
"Mitochondrial fission is controlled by dynamin-like proteins, the dysregulation of which is correlated with diverse diseases. Fission dynamin-like proteins are GTP hydrolysis-driven mechanoenzymes that self-oligomerize into helical structures that constrict membranes to achieve fission while also remodeling membranes by inducing negative Gaussian curvature, which is essential for the completion of fission.
Despite advances in optical and electron imaging technologies, the underlying mechanics of mitochondrial fission remain unclear due to the multiple times involved in the dynamics of mechanoenzyme activity, oligomer disassembly, and membrane remodeling.
Here, we examine how multiscale phenomena in dynamin Drp1 synergistically influence membrane fission using a mechanical model calibrated with small-angle X-ray scattering structural data and informed by a machine learning analysis of the Drp1 sequence, and tested the concept using optogenetic mechanostimulation of mitochondria in live cells.
We find that free dynamin-like proteins can trigger a “snap-through instability” that enforces a shape transition from an oligomer-confined cylindrical membrane to a drastically narrower catenoid-shaped neck within the spontaneous hemi-fission regime, in a manner that depends critically on the length of the confined tube.
These results indicate how the combination of assembly and paradoxically disassembly of dynamin-like proteins can lead to diverse pathways to scission."
From the abstract (2):
"Dynamin-related protein (Drp1) drives mitochondrial fission, dysregulation of which leads to neurodegenerative, metabolic, and apoptotic disorders. The precise mechanism of fission completion is unclear.
One prevailing model is based on GTP-driven assembly of Drp1 helices that increase confinement via force generation. However, constriction to nanoscopic tubule radii appears necessary but not sufficient for scission.
The other is based on GTP-driven disassembly of a constricting Drp1 scaffold that drives a membrane disturbance, but the relation of disassembly to scission and GTP hydrolysis remain uncertain.
Elucidation of mitochondrial fission is complicated by the multiple time-involved in the dynamics of mechanoenzyme activity, oligomer disassembly, and membrane remodeling.
Using machine learning, synchrotron X-ray scattering, and a theoretical model, our data support a model where progressive GTP hydrolysis enables free Drp1s to increase their capacity for inducing membrane negative Gaussian curvature (NGC).
Furthermore, we identify Drp1 variants that diminish this progressive capacity. Machine learning reveals that predicted NGC-generating sequences of the Drp1 oligomer are not in contact with the confined lipid tube and that scission-enhancing membrane remodeling is triggered by free Drp1 released upon disassembly."
1) Dynamin-like Proteins Combine Mechano-constriction and Membrane Remodeling to Enable Two-Step Mitochondrial Fission via a “Snap-through” Instability (open access)
2) Drp1 Proteins Released from Hydrolysis-Driven Scaffold Disassembly Trigger Nucleotide-Dependent Membrane Remodeling to Promote Scission (open access)
Graphical abstract (1)
Graphical abstract (2)
Figure 1. Drp1 has an intrinsic ability to induce negative Gaussian curvature.
No comments:
Post a Comment