Researchers in the field of neurodegeneration here provide evidence for supporting cells in the brain, specifically microglia, to use their own mitochondria as a form of signaling. Mitochondria are the power plants of the cell, responsible for packaging chemical energy store molecules. Their function declines with age for a range of poorly understood reasons, and this is important in numerous age-related conditions, particularly those in energy hungry tissues such as the brain. The researchers here report that microglia eject both whole and fragmentary mitochondria that other cells react to. Where the microglia are stressed, these ejected mitochondria are more often fragmentary, and are harmful to the surrounding environment.
This is all quite fascinating, given (a) past work on the ability of cells to take up mitochondria from their surroundings or pass mitochondria between one another, and (b) the growing body of evidence showing that senescent microglia are important in the progression of numerous age-related neurodegenerative conditions. Senescent cells, of course, cause harm to their surroundings via active signaling, consisting of secreted molecules and extracellular vesicles - and perhaps also mitochondria.
Researchers report that when microglia spat out damaged mitochondria, these cast-offs inflamed astrocytes, which in turn expelled their own mitochondrial fragments. Jetsam from either cell sickened neurons as well, limiting their energy production. Conversely, an inhibitor of mitochondrial fission protected astrocytes and neurons from the effect of externally added mitochondrial fragments, suggesting that mitochondrial fragmentation cascades from cell to cell. Curiously, adding whole, functional mitochondria to neuronal cultures mitigated the damage from fragmented organelles. Mitochondria are ancient bacterial invaders of eukaryotic cells, but are tolerated by the body because they are sequestered inside cells. Once released, their proteins and other macromolecules may trigger inflammation.
In mouse models of neurodegenerative conditions, P110 improved survival and motor skills. Exactly how P110 protected neurons in these mouse models was unclear. Researchers added the inhibitor to microglia expressing a 73-amino-acid polyglutamine expansion (Q73) that causes mitochondria to malfunction and fragment. P110 treatment reduced mitochondrial fission, boosted ATP production, and lowered reactive oxygen species. How might microglia in these models affect other cell types? The authors added media from Q73 microglia to mouse primary astrocyte cultures. In response, the astrocytes pumped out TNF-α and IL-1β. Their mitochondria became dysfunctional and fragmented, and 75 percent more astrocytes died. Adding P110 directly to astrocytes also protected them from the Q73 microglia-conditioned media.
Taken together, the data implied that fragmentation of mitochondria causes microglia and astrocytes to release factors that can somehow damage mitochondria in other cell types. The authors wondered if those released "factors" might be mitochondria themselves. Confirming this, the authors found intact functional mitochondria in media from healthy microglial cultures. Media from Q73 microglia cultures contained the same total number of mitochondria as media from the healthy cultures, but only half as many were whole and functional. At the same time, the amount of free-floating mitochondrial proteins in Q73 culture medium rose, suggesting the organelles were leaking contents. Treating Q73 microglial cultures with P110 bumped the number of functional mitochondria almost back to that of control cultures.
While the damaged organelles may trigger inflammation by activating microglia or astroglia, their direct effect on neurons remains puzzling, as does the effect of whole mitochondria. Researchers are investigating the idea that neurons take up whole or fragmented organelles, with the former bolstering cellular respiration and the latter spreading damage.