One crucial role that has emerged is in promoting the differentiation of various types of stem cell, including those for blood and fat cells — and, most recently, for neurons.
For stem cells, the primary means of producing energy is glycolysis, a process that generates ATP in the cytoplasm, rather than oxidative phosphorylation, the mitochondria-dependent method preferred by most mature, specialized cells. Why the cells differ in this way is not known: It may have something to do with the rate or byproducts of each process. But whatever the reasons, for a long time that difference obscured the role of mitochondria in stem cells, says Mireille Khacho , a cell biologist at the University of Ottawa.
But if they instead differentiate into specific lineages, they shift their primary source of fuel from glycolysis to oxidative phosphorylation. Because the latter process generates more ATP, scientists initially believed that the cellular transformation must have high energy requirements that mandate the transition. This thinking began to change in the early s, however, when findings from a handful of papers suggested that the mode of metabolism can directly influence decisions about cell fate.
In one key paper from , researchers studied how to reprogram adult cells to become induced pluripotent stem cells, which, like embryonic stem cells, can proliferate and mature into almost any cell type. They revealed that for this transformation to occur, the cells had to shift from oxidative phosphorylation to glycolysis. Until that revelation, most stem cell biologists had been focused on the genetic and epigenetic modifications that control the cell identity transitions, says Clifford Folmes , a mitochondrial researcher at the Mayo Clinic in Phoenix, Arizona, who was one of the co-authors of that study.
But that paper and others like it have made a case that changes in mitochondrial function may actually be key drivers of the process. The discovery that mitochondria might control the reprogramming of cells drove Khacho and Ruth Slack , her postdoctoral adviser at the University of Ottawa, to further investigate the role of the organelles in neuronal stem cells.
In , Slack, Khacho and their colleagues reported the first evidence that mitochondrial shape-shifting is a key regulator of neural stem cell fate , the decision to self-renew or differentiate. A loss of fission proteins, on the other hand, stimulated the stem cells to self-renew.
Given the previously established link between alterations in the fission and fusion machinery and neurodegenerative disorders, the team also investigated whether disrupting mitochondrial dynamics could alter the production of new neurons.
Prigione also advises caution in drawing conclusions about humans based on results from studies of neurogenesis in rodents. This is a particularly important consideration in studies conducted in mature animals, he says, because the question of whether the adult human brain generates new neurons at all is still a matter of debate.
Other research groups have also found that mitochondrial shape-shifting controls the fate of stem cells, but there seem to be notable dissimilarities across the array of stem cell varieties and experimental conditions. Studies on most types of stem cells show that their mitochondria are sparse and fragmented, but that they progressively elongate as the cells differentiate. But Slack and Khacho saw the opposite in neural stem cells from rodents: In their work, mitochondria start off elongated in the stem cells, then become fragmented in progenitor cells which are more committed to a specific cell fate before becoming elongated again as they differentiate into neurons.
Fission and fusion are happening all the time, and so far, scientists have only been looking at snapshots of this process. Mitochondrial dynamics are clearly important for stem cell function in general, according to David Chan , who leads a lab that studies them at the California Institute of Technology — but the dynamics are especially complicated in neural stem cells.
Exactly how mitochondrial shape-shifting can control decisions about cell fate is an open question. Findings from Slack, Khacho and their colleagues suggest that changes in mitochondrial structure could modify the amount of ROS in cells. But ROS is probably only part of the answer. Mitochondria can communicate with the cell in many ways , such as through the generation of other metabolites, the release and uptake of calcium, and changes in membrane potential. Both Slack and Khacho are searching for other mitochondrial metabolites that might be involved in stem cell fate.
Khacho, who now leads her own lab at the University of Ottawa, has moved on from neural stem cells to ones for muscle, and she hopes to identify similarities in mitochondrial dynamics and ROS signaling in another cell type. Get highlights of the most important news delivered to your email inbox. We do not yet know exactly how phospholipid bilayers are deformed during this process to allow membrane topology rearrangement.
Curiously, researchers who made yeast strains with fluorescently tagged Dnm1 found that not all the protein in the cell associates with mitochondria Otsuga et al. Some of it was observed in the cytoplasm, while some was in clumps on the mitochondrial surface at mitochondrial division sites.
Perhaps this is not surprising, since the protein does not include a transmembrane domain and is therefore not expected to be permanently anchored in a membrane on its own. For example, mitochondria break into smaller pieces early in programmed cell death apoptosis.
Regulation of these three mitochondrial shaping proteins occurs in different ways in various cell contexts and at many levels, including protein stability , protein cleavage , protein conformation via covalent modification, and protein localization via association with binding partners.
The additional protein participants are too numerous to describe here. In brief, degradation of mitofusins by the ubiquitin-proteasome system determines their steady-state levels and thus influences mitochondrial fusion Cohen et al. Finally, the common motor neurodegenerative disorder Parkinson's disease appears to be related to the control of mitochondrial dynamics, at least in some patients. Normally, mitochondrial fusion enhances mitochondrial integrity by allowing component sharing across the tubular network.
However, fusion of highly damaged mitochondria to the network could be detrimental, since hobbled mitochondria generate reactive oxygen species that cause a chain reaction of damage.
Cells have mechanisms to segregate and degrade badly damaged mitochondria. In normal cells, PINK1 senses a membrane potential change on damaged mitochondria and recruits Parkin, which in turn ubiquitinates mitofusins. These damaged, ubiquitin-marked mitochondria are then targeted for degradation. A current hypothesis, not yet proven, is that alteration of mitofusins may also prevent damaged mitochondria from fusing to the healthy network. In Parkinson's patients with faulty PINK1 or Parkin, damaged mitochondria are not degraded and remain integrated in the network, leading to cell damage and neurodegeneration.
Mitochondrial fusion and division are mediated by several large GTPases whose combined effects lead to the dynamic mitochondrial networks seen in many cell types. Many additional protein participants modulate the activities of these proteins in various contexts. Several human genetic neurodegenerative diseases are associated with improper regulation of mitochondrial fusion or division.
Scientists are currently determining how the molecular shape changes of these GTPases control the precise three-dimensional arrangement of phospholipids during fusion or division. Scientists are also searching for additional ways in which these fusion and division mediators are regulated in different tissues, since each mechanism of regulation represents a possible therapeutic target for patients with related disorders. Alexander, C.
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