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Joshi AU, Minhas PS, Liddelow SA, Haileselassie B, Andreasson KI, Dorn GW 2nd, Mochly-Rosen D. Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat Neurosci. 2019 Oct;22(10):1635-1648. Epub 2019 Sep 23 PubMed. Correction.
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National Institutes of Health
This very interesting article from lead author Amit Joshi adds to growing evidence that damaged mitochondria may propagate neurodegeneration by triggering neuroinflammation. Mitochondria are bacterial in origin. Their unique proteins, lipids, and circular DNA are usually protected from the innate immune system by two membranes within the cell. When damaged they may release bacterial-like macromolecules from this privileged space to be recognized by the immune system and incite inflammation. In the context of Parkinson’s disease, two recent papers in Nature (Sliter et al., 2018; Matheoud et al., 2019) demonstrated that damaged mitochondria in mice lacking the PD gene PINK1 trigger neuroinflammation through recognition of released mitochondrial DNA and display of mitochondrial antigens.
This article from Joshi et al. expands on this theme, showing that in microglia, the brain’s resident immune cells, mitochondria are damaged by neurotoxic proteins such as Aβ and that the damaged mitochondria release fragments into the extracellular milieu, activating astrocytes and causing neuronal death. Mitochondria have long been recognized to be important players in neurodegeneration, but the precise mitochondrial vulnerability has been unclear. This and other recent work suggest that the key may be recognition of these ancient mitochondrial invaders by the immune system.
References:
Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, Burman JL, Li Y, Zhang Z, Narendra DP, Cai H, Borsche M, Klein C, Youle RJ. Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018 Sep;561(7722):258-262. Epub 2018 Aug 22 PubMed.
Matheoud D, Cannon T, Voisin A, Penttinen AM, Ramet L, Fahmy AM, Ducrot C, Laplante A, Bourque MJ, Zhu L, Cayrol R, Le Campion A, McBride HM, Gruenheid S, Trudeau LE, Desjardins M. Intestinal infection triggers Parkinson's disease-like symptoms in Pink1-/- mice. Nature. 2019 Jul;571(7766):565-569. Epub 2019 Jul 17 PubMed.
View all comments by Derek NarendraNational Institute on Aging
The work from Joshi et al. provides an interesting mechanistic hypothesis to explain how multiple cell types may contribute to several different neurodegenerative diseases. That non-neuronal cells contribute to neuronal cell loss probably has been best established in SOD1-ALS but is also likely to be true in other diseases. Given that the genes influencing monogenic forms of AD, ALS, and HD are all different and are associated with different phenotypes in humans and the mouse models used here, my interpretation of the data presented here is that the mitochondrial pathway is likely to be a late common pathway for neuronal damage rather than an initiating event.
It might therefore be interesting to look at the role of mitochondrial-mediated activation in those diseases that appear to spread throughout the brain. It would also be important to establish whether cell-type restricted expression of P110 in vivo would be sufficient to block cell death as it does in the primary culture experiments reported here.
View all comments by Mark CooksonMake a Comment
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