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Review
. 2021 Mar 16:12:624919.
doi: 10.3389/fimmu.2021.624919. eCollection 2021.

Unraveling the Link Between Mitochondrial Dynamics and Neuroinflammation

Lilian Gomes de Oliveira  1   2 , Yan de Souza Angelo  1   2 , Antonio H Iglesias  3 , Jean Pierre Schatzmann Peron  1   2   3
Affiliations
Review

Unraveling the Link Between Mitochondrial Dynamics and Neuroinflammation

Lilian Gomes de Oliveira et al. Front Immunol. .

Abstract

Neuroinflammatory and neurodegenerative diseases are a major public health problem worldwide, especially with the increase of life-expectancy observed during the last decades. For many of these diseases, we still lack a full understanding of their etiology and pathophysiology. Nonetheless their association with mitochondrial dysfunction highlights this organelle as an important player during CNS homeostasis and disease. Markers of Parkinson (PD) and Alzheimer (AD) diseases are able to induce innate immune pathways induced by alterations in mitochondrial Ca2+ homeostasis leading to neuroinflammation. Additionally, exacerbated type I IFN responses triggered by mitochondrial DNA (mtDNA), failures in mitophagy, ER-mitochondria communication and mtROS production promote neurodegeneration. On the other hand, regulation of mitochondrial dynamics is essential for CNS health maintenance and leading to the induction of IL-10 and reduction of TNF-α secretion, increased cell viability and diminished cell injury in addition to reduced oxidative stress. Thus, although previously solely seen as power suppliers to organelles and molecular processes, it is now well established that mitochondria have many other important roles, including during immune responses. Here, we discuss the importance of these mitochondrial dynamics during neuroinflammation, and how they correlate either with the amelioration or worsening of CNS disease.

Keywords: Alzheimer disease; Parkinson disease; mitochondria; multiple sclerosis; neurodegenerative diseases; neuroinflammation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Mitochondrial alterations in protective and detrimental processes within CNS. Alterations in mitochondrial dynamics may induce either harmful or helpful immune responses affecting in CNS homeostasis. (A) Amyloid-β and α-synuclein induces TLR-2 and TLR-4 activation, respectively, promoting the interaction between outer mitochondria membrane (OMM) and endoplasmic reticulum (ER) membrane to synergically increase Ca2+ uptake and NFAT activation. (B) Type I IFN production is induced by mtDNA activation of cGAS-STING during sustained mitochondrial damage promoting neurodegeneration. (C) STING may also induce activation of NLRP3. (D) The NLRP3 may also be induced by mtROS thus coordinating IL-1β secretion by microglia and astrocytes promoting neuronal loss. (E) Amyloid-β aggregates induce NLRP3 inflammasome activation and IL-1β secretion by microglia. (F) mtROS induces cardiolipin peroxidation that deregulates ATP production, as observed during aging. (G) In neurons, BAX interacts with DRP1 inducing mitochondrial fragmentation. This is critical for BAX-dependent pore formation and neuronal survival. (H) Failure in mitophagy culminates in damaged mitochondria accumulation which contributes for Parkinson’s disease (PD) progress. (I) Mitophagy may be induced by IFN-γ and LPS upregulation of DRP1 and LC3, an autophagy-related protein. This is essential to restore tubular mitochondrial networks after inflammatory stimulation in astrocytes. (J) Microglial cells under mitophagy have elevated levels of intracellular Aβ aggregates, suggesting increased phagocytic activity, and thus clearing the harmful Aβ deposits. (K) PINK1 regulation of mitophagy is essential for CNS homeostasis establishment and induction of IL-10 and reduction of TNF-α secretion. (L) Instead of mitophagy the release of damage mitochondria may also minimize overall cell injury. Conversely, healthy mitochondria may also be donated from astrocytes to damaged neighboring neurons increasing its viability and maintaining its metabolism. (M) Cardiolipin can interact with α-synuclein preventing its aggregation by modifying its structure and impairing the release of cytosolic cytochrome c and thus inhibiting apoptosis and dampening cellular oxidative stress. Illustration prepared by the authors using www.biorender.com.
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