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Mitochondrial Micrornas in Aging and Neurodegenerative Diseases

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Mitochondrial Micrornas in Aging and Neurodegenerative Diseases cells Review Mitochondrial MicroRNAs in Aging and Neurodegenerative Diseases Albin John 1, Aaron Kubosumi 1 and P. Hemachandra Reddy 1,2,3,4,5,* 1 Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; [email protected] (A.J.); [email protected] (A.K.) 2 Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA 3 Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA 4 Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA 5 Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA * Correspondence: [email protected]; Tel.: +1-806-743-3194 Received: 7 April 2020; Accepted: 27 May 2020; Published: 28 May 2020 Abstract: MicroRNAs (miRNAs) are important regulators of several biological processes, such as cell growth, cell proliferation, embryonic development, tissue differentiation, and apoptosis. Currently, over 2000 mammalian miRNAs have been reported to regulate these biological processes. A subset of microRNAs was found to be localized to human mitochondria (mitomiRs). Through years of research, over 400 mitomiRs have been shown to modulate the translational activity of the mitochondrial genome. While miRNAs have been studied for years, the function of mitomiRs and their role in neurodegenerative pathologies is not known. The purpose of our article is to highlight recent findings that relate mitomiRs to neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s. We also discuss the involvement of mitomiRs in regulating the mitochondrial genome in age-related neurodegenerative diseases. Keywords: microRNAs; mitochondrial microRNAs; aging; Alzheimer’s disease; Parkinson’s disease; Huntington’s disease; oxidative stress; mitochondrial function and mitophagy 1. Introduction Since their incorporation into eukaryotes billions of years ago, mitochondria have evolved into the source of energy for cell survival [1]. This energy, in the form of adenosine triphosphate (ATP), powers most cellular processes. Given their origin as independent prokaryotes, mitochondria maintain their own circular DNA separate from somatic DNA [1]. However, the proteins that participate in mitochondrial function come from both nuclear and mitochondrial genomes. This interplay that takes place in the symbiotic relationship between cell and mitochondria results in its peculiar structure and subsequent function [1–5]. Mitochondria perform multiple cellular functions, including ATP production, intracellular calcium regulation, apoptotic cell death, free radicals generation and scavenging, and the activation of the caspase family of proteases in apoptosis [1]. A mitochondrion is comprised of an outer membrane, an inner-membrane, and a matrix where its genome, ribosomes, and other structures lie. The intermembrane space is between the outer and inner membranes (Figure1). The outer membrane is porous and contains proteins, called porins, that allow for the unfettered movement of ions and small, uncharged molecules into the intermembrane space [1–5]. Larger molecules and proteins must pass through translocase complexes to bypass the Cells 2020, 9, 1345; doi:10.3390/cells9061345 www.mdpi.com/journal/cells Cells 2020, 9, 1345 2 of 18 outer membrane in order to access the intermembrane space. In contrast, the inner membrane serves as Cells 2020, 9, x 2 of 19 a tight barrier around the matrix of the mitochondrion and only allows molecules and proteins access accessvia membrane-transfervia membrane-transfer proteins proteins that are that selective are forselective specific for ions specific and proteins ions [6and]. Invaginations proteins [6] of. the Invaginationsinner membrane, of the calledinner cristae,membrane, allow called for increased cristae, production allow for ofincreased ATP by increasingproduction the of surface ATP by area of increasingthe inner the membrane surface area [2 ].of the inner membrane [2]. Figure 1. Mitochondrial structure. Schematic of the mitochondrion showing the electron transport Figurechain, 1. M flowitochon of ions,drial and structure. generation Schematic reactive of oxidative the mitochondrion species. These showing reactive the oxidative electron speciestransport can be chain,reduced flow of to ions, hydrogen and generation peroxide reactive via the SOD2oxidative enzyme species. and These further reactive broken oxidative down into species H2O can and be O 2 by reducedthe GPXto hydrogen enzyme. peroxide However, via the the reduction SOD2 enzyme process and is not further perfect broken and when down under into H high2O and stress, O2 reactiveby the GPXoxidative enzyme. species However, can leak the out reduction of the mitochondria. process is not Theperfect mitochondria and when areunder also high important stress, regulatorsreactive of oxidativeintracellular species calciumcan leak concentration.out of the mitochondria. The mitochondria are also important regulators of intracellular calcium concentration. The division between the matrix and intermembrane space allows the mitochondria to perform its mostThe division important between function the of matrix ATP production and intermembrane [2]. The tightness space ofallows the inner the mitochondria membrane allows to perform proteins to its mostpump important hydrogen function ions out of theATP matrix production and into [2] the. The intermembrane tightness of spacethe inner to create membrane an electrochemical allows proteinsgradient to pump (Figure hydrogen1). ATP synthaseions out utilizesof the matrix this electrochemical and into the intermem gradientbrane to produce space ATP to create in a process an electrochemicalcalled oxidative gradient phosphorylation (Figure 1). ATP [1]. synthase In addition utilizes to ATP this production, electrochemical the mitochondriagradient to produce play a key ATProle in ina cellprocess signaling called and oxidative cellular diphosphorylationfferentiation. As [1] a result,. In addition mitochondrial to ATP dysregulation production, is the largely mitochondriaimplicated play in aging a key androle neurodegenerativein cell signaling and diseases cellular [ 7differentiation.]. The purpose As of a this result, article mitochondrial is to review the dysregulationlatest developments is largely implicated in mitochondrial in aging microRNAs and neurodegenerative (miRNAs) research diseases in neurodegenerative[7]. The purpose of diseases.this articleThis is articleto review also focusesthe latest on thedevelopments role of mitochondrial in mitochondrial microRNA microRNAs in neurodegenerative (miRNAs) diseasesresearch suchin as neurodegenerativeParkinson’s, Alzheimer’s diseases. This and Huntington’s.article also focuses on the role of mitochondrial microRNA in neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s. 2. MicroRNAs 2. MicroRNAsMicroRNAs (miRNAs) are small, noncoding RNA molecules that are 18–25 nucleotides in length andMicroRNAs act as post-transcriptional (miRNAs) are small, regulators noncoding of RNA gene molecules expression. that Figure are 128 –summarizes25 nucleotides the in biogenesis length and ofact miRNAs as post-transcriptional from the nucleus. regulators RNA of polymerase gene expression. II produces Figure primary 2 summarizes miRNAs the (pri-miRNAs)biogenesis of [8]. miRNAsThese from pri-miRNAs the nucleus. are processedRNA polymerase inside the II produces nucleus by primary the drosha miRNAs protein (pri that-miRNAs produces) [8] a. These precursor pri-miRNAsmiRNA (pre-miRNA)are processed [8 ].inside Pre-miRNA the nucleu is mores by stable the drosha than pri-miRNA protein that because produces of its hairpina precursor structure. miRNAThe ( pre-miRNApre-miRNA) is [8] then. Pre exported-miRNA is to more the cytoplasm stable than by pri exportin-miRNA 5,because which of recognizes its hairpin a structure. 2-nucleotide The overhangpre-miRNA from is then the hairpin exported loop. to the It is cytoplasm then spliced by by exportin the dicer 5, RNAsewhich recognizes and one strand a 2-nucleotide is chosen due overhangto its greaterfrom the thermodynamic hairpin loop. It stabilityis then spliced [9]. The by chosen the dicer strand, RNAse or and the matureone strand miRNA, is chosen binds due to the to itsRNA-induced greater thermodynamic silencing complex stability (RISC). [9]. The chosen strand, or the mature miRNA, binds to the RNA-induced silencing complex (RISC). Cells 2020, 9, 1345 3 of 18 Cells 2020, 9, x 3 of 19 FigureFigure 2. Production 2. Production and andimport import of mitomiRNA. of mitomiRNA. MicroRNAsMicroRNAs can can be found be found in multiple in multiple organelles. organelles. Researchers Researchers hypothesized hypothesized that that the theregion region near near the the3′ end 30 end of the of themiRNA miRNA may may contain contain information information on intracellular on intracellular target target location. location. This This finding finding is not is not absoluteabsolute as some as some miRNAs, miRNAs, such such as miR as miR-181,-181, can can localize localize in both in both the thecytoplasm cytoplasm (miR (miR-181a)-181a) as well as well as as the themitochondria mitochondria (miR (miR-181c)-181c) despite despite having having the thesame same 3′ motif. 30 motif. Regardless, Regardless, there there are areseveral several pathways pathways
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