Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Jul 22;9(8):647.
doi: 10.3390/antiox9080647.

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

Anna Picca  1 , Riccardo Calvani  1 , Hélio José Coelho-Junior  2 , Francesco Landi  1   2 , Roberto Bernabei  1   2 , Emanuele Marzetti  1   2
Affiliations
Review

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

Anna Picca et al. Antioxidants (Basel). .

Abstract

Oxidative stress develops as a response to injury and reflects a breach in the cell's antioxidant capacity. Therefore, the fine-tuning of reactive oxygen species (ROS) generation is crucial for preserving cell's homeostasis. Mitochondria are a major source and an immediate target of ROS. Under different stimuli, including oxidative stress and impaired quality control, mitochondrial constituents (e.g., mitochondrial DNA, mtDNA) are displaced toward intra- or extracellular compartments. However, the mechanisms responsible for mtDNA unloading remain largely unclear. While shuttling freely within the cell, mtDNA can be delivered into the extracellular compartment via either extrusion of entire nucleoids or the generation and release of extracellular vesicles. Once discarded, mtDNA may act as a damage-associated molecular pattern (DAMP) and trigger an innate immune inflammatory response by binding to danger-signal receptors. Neuroinflammation is associated with a large array of neurological disorders for which mitochondrial DAMPs could represent a common thread supporting disease progression. The exploration of non-canonical pathways involved in mitochondrial quality control and neurodegeneration may unveil novel targets for the development of therapeutic agents. Here, we discuss these processes in the setting of two common neurodegenerative diseases (Alzheimer's and Parkinson's disease) and Down syndrome, the most frequent progeroid syndrome.

Keywords: Alzheimer’s disease; DAMPs; Down syndrome; Parkinson’s disease; cytokines; endo-lysosomal system; extracellular vesicles; mitochondrial DNA; mitochondrial quality control; mitophagy.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Schematic representation of the pathways involved in mitochondrial DNA unloading. Under several stressors (e.g., mitochondrial dysfunction and consequent reactive oxygen species (ROS) production, viral and bacterial infections), several types of damage are inflicted to mitochondrial DNA (mtDNA) and a set of signaling pathways are activated to promote mitochondrial recovery or demise depending on the damage severity. (1) In the setting of ROS bursts, mtDNA oxidation and fragmentation occur concomitant with mitochondrial permeability transition pore (mPTP) opening. If the extent of damage overwhelms the mitochondrial quality control system, persistent mPTP opening allows extrusion of oxidized mtDNA fragments into the cytosol. Meanwhile, the deployment of apoptosis via Bax/Bak signaling enables the extrusion of mtDNA nucleoids consisting of mitochondrial transcription factor A-bound mtDNA. (2) Transient opening of mPTP and ROS production trigger mitochondrial fission and mitophagy to clear dysfunctional mitochondria. Damaged organelles are sequestered into autophagosomes that subsequently fuse with lysosomes for content disposal. Herein, a set of DNases execute mtDNA cleavage. (3) Hyperfragmented or hyperfused mitochondria also deliver mtDNA into the cytosol from which it can be extruded into the extracellular space through unknown mechanisms. (4) If mitochondria are only mildly damaged, mtDNA and other mitochondrial constituents can be shuttled outside the cell via extracellular vesicles (EVs). EVs of mitochondrial origin (i.e., mitochondrial derived vesicles) may fuse with multivesicular bodies (MVBs) and deliver their cargo in the extracellular space for signaling purposes. (5) Following cell injury or necrosis, the damaged plasma membrane may represent a route for the delivery of mtDNA and other cellular components outside of the cell. Abbreviations: LC3, microtubule-associated protein 1A/1B-light chain 3; PARL, presenilin-associated rhomboid-like; PINK, phosphatase and tensin homolog-induced kinase 1; TIM, translocase of the inner mitochondrial membrane; TOM, translocase of the outer mitochondrial membrane.
Figure 2
Figure 2
Signaling pathways whereby damaged-associated molecular patterns can trigger inflammation. Failing mitochondrial quality control processes may lead to intracellular accrual of damaged components and their release as damaged-associated molecular patterns (DAMPs). Acting as a DAMP, oxidized mitochondrial DNA (mtDNA) either in the form of mitochondrial transcription factor A-bound nucleoids (green circles) or free mtDNA (red circles) can trigger inflammation via interacting with (1) toll-like receptors (TLRs), (2) nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, and (3) cytosolic cyclic GMP/AMP synthase (cGAS)–stimulator of interferon genes (STING) DNA-sensing system. Abbreviations: IFN, interferon; IL, interleukin; IRF-1, interferon regulatory factor 1; mtDNA, mitochondrial DNA; NF-κB, nuclear factor κB; ROS, reactive oxygen species; TBK1, TRAF family member-associated NF-κB activator (TANK)-binding kinase 1; TNF-α, tumor necrosis factor alpha.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Giasson B.I., Duda J.E., Murray I.V.J., Chen Q., Souza J.M., Hurtig H.I., Ischiropoulos H., Trojanowski J.Q., Lee V.M.Y. Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions. Science. 2000;290:985–989. doi: 10.1126/science.290.5493.985. - DOI - PubMed
    1. Fischer R., Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: Role of TNF. Oxid. Med. Cell. Longev. 2015;2015:610813. doi: 10.1155/2015/610813. - DOI - PMC - PubMed
    1. Chausse B., Lewen A., Poschet G., Kann O. Selective inhibition of mitochondrial respiratory complexes controls the transition of microglia into a neurotoxic phenotype in situ. Brain. Behav. Immun. 2020 doi: 10.1016/j.bbi.2020.05.052. online ahead of print. - DOI - PubMed
    1. Calvani R., Picca A., Marini F., Biancolillo A., Gervasoni J., Persichilli S., Primiano A., Coelho-Junior H.J., Bossola M., Urbani A., et al. A distinct pattern of circulating amino acids characterizes older persons with physical frailty and sarcopenia: Results from the BIOSPHERE Study. Nutrients. 2018;10:1691. doi: 10.3390/nu10111691. - DOI - PMC - PubMed
    1. DiSabato D.J., Quan N., Godbout J.P. Neuroinflammation: The devil is in the details. J. Neurochem. 2016;139:136–153. doi: 10.1111/jnc.13607. - DOI - PMC - PubMed

LinkOut - more resources

-