Mitochondria fragments fuel the fire of neuroinflammation

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Science Translational Medicine  02 Oct 2019:
Vol. 11, Issue 512, eaaz3714
DOI: 10.1126/scitranslmed.aaz3714


Mitochondrial fragmentation in glial cells appears to induce an inflammatory state capable of propagating.

The mitochondria are organelles in cells that perform cellular respiration, providing the necessary energy for cellular functions. Extensive evidence from clinical studies to animal models suggest mitochondrial fission leading to fragmentation plays a critical role in several degenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Excess production of dynamin-related protein (Drp1)–induced mitochondrial fission is also a pathological feature in mouse models of AD, ALS, and HD. Inhibiting the binding of Drp1 to mitochondrial fission 1 (Fis1) with a heptapeptide (P110) has been shown to slow disease progression in these mouse models.

These studies have provided evidence for mitochondrial fragmentation as a critical component of the neurodegenerative process. To investigate the role mitochondrial fragmentation plays in neuroinflammation, Joshi et al. subjected P110-treated samples in mouse models of AD, ALS, or HD to histological analyses for astrocytic and microglial markers, revealing that gliosis was suppressed. Inflammatory gene expression analyses corroborated that P110 treatment inhibited neuroinflammation. Studies in the microglial cell line BV2, expressing mutant SOD1-G93A as a model for ALS, or a long track of neurotoxic polyglutamine (Q73) as a model for HD, revealed mitochondrial fragmentation and increased cytokine production. Similarly, treating microglia with oligomeric β-amyloid as a model for AD induced mitochondrial fragmentation and microglial activation. Conversely, P110 treatment attenuated the mitochondrial fragmentation and suppressed activation, suggesting mitochondria fragmentation drives microglia activation. Secreted dysfunctional mitochondria were present in activated microglial-conditioned media (MCM), and treating primary astrocytes with MCM led to mitochondrial fragmentation and an activation state putatively termed A1. These features were also attenuated by P110 treatment. Activated astrocytes also secreted dysfunctional mitochondria and transferring conditioned media to primary neurons evoked neuronal damage. To evaluate the contribution of dysfunctional mitochondria on neuronal damage, the authors filtered out mitochondria particles from the activated astrocyte-conditioned media, which lessened the neuronal cell death.

These analyses suggested the propagation of the inflammatory response from microglia to astrocytes are in part mediated by mitochondria fragments, which in turn spur a neurotoxic response. Future studies should evaluate the effects of reactive astrocytes on microglia as the neuroinflammatory system is a network of signals. It is important to stress that there are likely several distinct populations of astrocytes, and clarity is needed before fully understanding their reactivity. It is imperative that further studies should determine if this mechanism recapitulates in vivo as these studies are cell-cultured based.

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