Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration
Authors: Bereketeab Haileselassie
Gerald W Dorn 2nd
Shane A Liddelow
Daria Mochly-Rosen
Amit U Joshi
Katrin I Andreasson
Paras S Minhas
Journal: Nature Neuroscience (2019)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: neurodegenerative diseases; glia-mediated neuroinflammation; neurotoxic proteins; microglia; neuronal death
Affiliations: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA., Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA., Department of Neuroscience and Physiology and Neuroscience Institute, New York University Langone Medical Center, New York, NY, USA., Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, Australia., Department of Pediatrics Division of Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA., Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA., Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA. .

Abstract:  In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria. 

Retracted: No

PubPeer comments:
  Fig 2, comparison between j and k. , 
 I noticed this too. Also, in panel f of the same Fig 2, the IL-1beta values look like the TNF-alpha values multiplied by 2 (except for the control group values, which look the same):  , 
 #1 Dear Streptococcus Ursoris, Thank you very much for pointing out the mistake of Fig 2, comparison between j and k in our published work. Somehow an error was introduced during figure preparations and I m extremely embarrassed that this wasn t picked up during the entire process. We are in touch with the editors at Nat Neuro. Here s the now corrected figure and raw data.   Best, Amit , 
 #2 Dear Passiflora Complanata, Thank you very much for pointing out the mistake of Fig 2 f in our published work. Somehow an error was introduced during figure preparation and I m extremely embarrassed that this wasn t picked up during the entire process. We are in touch with the editors at Nat Neuro. Here s the now corrected figure and raw data.   Best, Amit , 
 Methodologically, there is concern that the employed protocol for isolation of mitochondria released from microglia presents nothing else than a technical artefact resulting from the procedure employed to harvest cells and the subsequent manipulation steps (centrifugation). It s disappointing to see that more sophisticated and readily available protocols weren t employed, and that reviewers did not think this was a point of concern (for any mitochondrial scientist, it would be). As an example, it is noteworthy that the measured parameters (ATP etc.) are not in reference to total mitochondrial mass of the cell sample they were isolated from. Hence the general contribution and scale of these data from free mitochondria may be very small (depending on fragmentation of cells during isolation). However, I think the protocol may unintentionally stimulate the small possibility that that free mitochondria could be released in vivo as consequence of massive and uncontrolled cell death. But for now, the statement of immunogenic mitochondria is still rather hypothetical and due to the method chosen to isolate extracellular mitochondria, not supported by the data. Future will tell. ,