International Journal of Molecular Sciences Review Evidence for the Role of Mitochondrial DNA Release in the Inflammatory Response in Neurological Disorders Gonzalo E. Moya, Phillip D. Rivera * and Kristin E. Dittenhafer-Reed * Department of Chemistry and Biology, Hope College, Holland, MI 49423, USA; [email protected] * Correspondence: [email protected] (P.D.R.); [email protected] (K.E.D.-R.) Abstract: Mitochondria are regarded as the metabolic centers of cells and are integral in many other cell processes, including the immune response. Each mitochondrion contains numerous copies of mitochondrial DNA (mtDNA), a small, circular, and bacterial-like DNA. In response to cellular damage or stress, mtDNA can be released from the mitochondrion and trigger immune and inflam- matory responses. mtDNA release into the cytosol or bloodstream can occur as a response to hypoxia, sepsis, traumatic injury, excitatory cytotoxicity, or drastic mitochondrial membrane potential changes, some of which are hallmarks of neurodegenerative and mood disorders. Released mtDNA can mediate inflammatory responses observed in many neurological and mood disorders by driving the expression of inflammatory cytokines and the interferon response system. The current understand- ing of the role of mtDNA release in affective mood disorders and neurodegenerative diseases will be discussed. Keywords: mitochondrial DNA (mtDNA); mitochondria; inflammation; reactive oxygen species Citation: Moya, G.E.; Rivera, P.D.; (ROS); neurodegenerative disease; neuropsychiatric disorder Dittenhafer-Reed, K.E. Evidence for the Role of Mitochondrial DNA Release in the Inflammatory Response in Neurological Disorders. 1. Introduction Int. J. Mol. Sci. 2021, 22, 7030. https://doi.org/10.3390/ Mitochondria are the metabolic hubs in eukaryotic cells. These organelles produce ijms22137030 adenosine triphosphate (ATP) to fuel cellular functions and also play integral roles in multiple facets of metabolite processing (as reviewed in [1]). To maintain these functions, Academic Editor: Maria Simarro mitochondria rely on genetic information stored in the nucleus and their own small genome Grande (mtDNA). Mammalian cells possess numerous copies of mtDNA, a 16.6 kilobase (kb) circu- lar, double-stranded molecule encoding 13 proteins essential for electron transport and ATP Received: 11 May 2021 synthesis, 22 transfer RNAs, and 2 ribosomal RNAs (Figure1)[ 2]. The electron transport Accepted: 26 June 2021 chain, apart from being vital for the generation of the proton gradient that drives ATP Published: 29 June 2021 synthesis, is also the main generator of mitochondrial reactive oxygen species (mtROS). mtROS can act as an important redox signaling molecule, but exacerbated mtROS can Publisher’s Note: MDPI stays neutral lead to the damage of proteins, lipids, and nucleic acids that further drive mitochondrial with regard to jurisdictional claims in dysfunction and apoptosis (as discussed in [1]). The increase in oxidative damage due to published maps and institutional affil- elevated mtROS is thought to contribute to the progression of many diseases [3]. One out- iations. come of severe oxidative stress is the release of mtDNA from the mitochondria to the cytosol, which can be followed by extracellular release [4–6]. This extracellular release is of particular importance due to the implications of mtDNA mediating and/or contributing to inflammatory responses, driven by the bacterial-like nature of mtDNA [7]. In this review Copyright: © 2021 by the authors. we will discuss the ways in which mitochondria contribute to pro-inflammatory signaling Licensee MDPI, Basel, Switzerland. through mtDNA release, as well as the ways extra-mitochondrial mtDNA may contribute This article is an open access article to the progression of neurological disease. distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 7030. https://doi.org/10.3390/ijms22137030 https://www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci. Sci.2021 2021, ,22 22, 7030, 7030 22 of of 26 26 FigureFigure 1. 1.Overview Overview ofof mtDNA. mtDNA.Mitochondrial Mitochondrial DNADNA encodesencodes forfor 13 13 protein protein subunits subunits involved involved in in oxidativeoxidative phosphorylation phosphorylation (OXPHOS), (OXPHOS), the the main main energy-producing energy-producing pathway pathway of of the the cell. cell. The The diagram diagram depictsdepicts the the protein protein coding coding genes genes found found within within the the mitochondrial mitochondrial genome genome that that encode encode for for subunits subunits ofof OXPHOS OXPHOS complexes. complexes. GenesGenes areare colorcolor codedcoded toto correspondcorrespond toto thethe colorcolor ofof thethe OXPHOSOXPHOS complex.complex. The numbers reflect the number of protein subunits of each complex encoded by the mitochondria The numbers reflect the number of protein subunits of each complex encoded by the mitochondria out of the total number of protein subunits. The genetic instructions for the remaining subunits are out of the total number of protein subunits. The genetic instructions for the remaining subunits are carried in the nucleus. The 22 transfer RNAs encoded by the mitochondrial genome are not shown. carriedAbbreviations: in the nucleus. NADH The dehydrogenase/ 22 transfer RNAsComplex encoded I subunits by the (ND1 mitochondrial-6); Cytochrome genome oxidase/Complex are not shown. Abbreviations:III subunits (COX1 NADH-3); dehydrogenase/ComplexATP synthase subunits (ATP6, I subunits ATP8); (ND1-6); cytochrome Cytochrome b (CYTb). oxidase/Complex III subunits (COX1-3); ATP synthase subunits (ATP6, ATP8); cytochrome b (CYTb). 2. Mechanisms of Mitochondrial DNA Release 2. Mechanisms of Mitochondrial DNA Release 2.1.2.1. mtDNAmtDNA ReleaseRelease ininResponse Response to to Cellular Cellular Stress Stress MitochondriaMitochondria play play important important roles roles in in cellular cellular signaling. signaling. Recent Recent evidence evidence shows shows that that mitochondriamitochondria andand mtDNAmtDNA areare heavilyheavily involvedinvolved inin immunityimmunity andand inflammationinflammation (as(as dis-dis- cussedcussed inin [[8,9])8,9]).. Accumulation Accumulation of of oxidative oxidative damage damage in inthe the mitochondrion mitochondrion can can impa impairir res- respiratorypiratory function, function, eventually eventually leading leading to to oxidation oxidation of of mtDNA andand otherother mitochondrialmitochondrial componentscomponents [[10]10].. Due Due to to the the proximity proximity to to the the formation formation of ofROS ROS in the inthe mitochondrial mitochondrial ma- matrix,trix, mtDNA mtDNA is issusceptible susceptible to tonumerous numerous forms forms of of oxidative oxidative damage damage,, including including chemi chemi-cal calmodification modification to tonucleotide nucleotide bases bases and and the the sugar sugar backbone, backbone, as wellwell asas double-strandeddouble-stranded breaksbreaks [11[11]].. Mitochondria Mitochondria possesspossess repairrepairmechanisms mechanisms forfor thesetheseoxidative oxidative lesions,lesions, includ-includ- inging many many pathways pathways akin akin to thoseto those found found in the in nuclearthe nuclear DNA DNA damage damage response response (as reviewed (as re- invi [ewed12]). Whenin [12] damage). When accumulates damage accumulates beyond the beyond capacity the of capacity these repair of these systems, repair mitochon- systems, driamitochondria can be selectively can be selectively degraded bydegraded macroautophagy, by macroautophagy, the cellular the recycling cellularsystem recycling [13, 14sys-]. Thetem degradation [13,14]. The ofdegradation mitochondria of mitochondria can lead to the can release lead oftomtDNA the release into of the mtDNA cytosol into where the itcytosol may activate where it a may broad activate range a of broad innate range cellular of innate responses cellular [15 responses,16]. Through [15,16] autophagy,. Through virtuallyautophagy, all cellular virtually components all cellular can components be degraded can in thebe lysosomedegraded [17in ].the A structurelysosome defined [17]. A asstructure the autophagosome defined as the is formed,autophagosome consisting is offormed, membrane consisting components of membrane of the endoplasmic components reticulumof the endoplasmic and several reticulum protein complexes. and several These protein proteins complexes. bind mitochondrial These proteins components, bind mito- targetingchondrial specific components, mitochondria targeting to bespecific encapsulated mitochondria within to the be autophagosome encapsulated within for degrada- the au- tiontophagosome [18]. In this for review, degradation we refer [18] to. mitophagyIn this review, as the we selective refer to turnovermitophagy of as mitochondria the selective throughturnover the of autophagicmitochondria pathway. through the autophagic pathway. Int. J. Mol. Sci. 2021, 22, 7030 3 of 26 An example of one of these essential protein complexes in mitophagy is the ubiquitin- carrier p62 [19]. Mitochondria are polyubiquitinated upon phosphorylation of p62, fol- lowing PTEN-induced kinase 1 (PINK1) non-canonical import into mitochondria [20]. PINK1 phosphorylates ubiquitin (Ub), essentially labelling mitochondria for degrada- tion. The PINK1-derived rise in poly-ubiquitin recruits the poly-ubiquitinase PARKIN, which amplifies the