Mitovesicles Are a Novel Population of Extracellular Vesicles of Mitochondrial Origin Altered in Down Syndrome

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 Feb 13

PMID 33579698

Citations 120

Authors

Pasquale DAcunzo

Rocio Perez-Gonzalez

Yohan Kim

Tal Hargash

Chelsea Miller

Melissa J Alldred

Hediye Erdjument-Bromage

Sai C Penikalapati

Monika Pawlik

Mitsuo Saito

Mariko Saito

Stephen D Ginsberg

Thomas A Neubert

Chris N Goulbourne

Efrat Levy

Affiliations

Soon will be listed here.

Abstract

Mitochondrial dysfunction is an established hallmark of aging and neurodegenerative disorders such as Down syndrome (DS) and Alzheimer's disease (AD). Using a high-resolution density gradient separation of extracellular vesicles (EVs) isolated from murine and human DS and diploid control brains, we identify and characterize a previously unknown population of double-membraned EVs containing multiple mitochondrial proteins distinct from previously described EV subtypes, including microvesicles and exosomes. We term these newly identified mitochondria-derived EVs "mitovesicles." We demonstrate that brain-derived mitovesicles contain a specific subset of mitochondrial constituents and that their levels and cargo are altered during pathophysiological processes where mitochondrial dysfunction occurs, including in DS. The development of a method for the selective isolation of mitovesicles paves the way for the characterization in vivo of biological processes connecting EV biology and mitochondria dynamics and for innovative therapeutic and diagnostic strategies.

Citing Articles

Mitochondrial Dysfunction Correlates with Brain Amyloid Binding, Memory, and Executive Function in Down Syndrome: Implications for Alzheimer's Disease in Down Syndrome.

Beresford-Webb J, McAllister C, Sleigh A, Walpert M, Holland A, Zaman S Brain Sci. 2025; 15(2).

PMID: 40002463 PMC: 11853603. DOI: 10.3390/brainsci15020130.

Recommendations for mitochondria transfer and transplantation nomenclature and characterization.

Brestoff J, Singh K, Aquilano K, Becker L, Berridge M, Boilard E Nat Metab. 2025; 7(1):53-67.

PMID: 39820558 DOI: 10.1038/s42255-024-01200-x.

Current trends in extracellular vesicle research on neuroscience from ADPD2021 meeting.

Ikezu T Extracell Vesicles Circ Nucl Acids. 2024; 2(1):49-54.

PMID: 39698505 PMC: 11651121. DOI: 10.20517/evcna.2021.08.

Extracellular vesicles, RNA sequencing, and bioinformatic analyses: Challenges, solutions, and recommendations.

Miceli R, Chen T, Nose Y, Tichkule S, Brown B, Fullard J J Extracell Vesicles. 2024; 13(12):e70005.

PMID: 39625409 PMC: 11613500. DOI: 10.1002/jev2.70005.

Unraveling the complexity of follicular fluid: insights into its composition, function, and clinical implications.

Pan Y, Pan C, Zhang C J Ovarian Res. 2024; 17(1):237.

PMID: 39593094 PMC: 11590415. DOI: 10.1186/s13048-024-01551-9.

References

Peng K, Perez-Gonzalez R, Alldred M, Goulbourne C, Morales-Corraliza J, Saito M . Apolipoprotein E4 genotype compromises brain exosome production. Brain. 2018; 142(1):163-175. PMC: 6308312. DOI: 10.1093/brain/awy289. View

Alldred M, E Duff K, Ginsberg S . Microarray analysis of CA1 pyramidal neurons in a mouse model of tauopathy reveals progressive synaptic dysfunction. Neurobiol Dis. 2011; 45(2):751-62. PMC: 3259262. DOI: 10.1016/j.nbd.2011.10.022. View

Ginsberg S, Alldred M, Counts S, Cataldo A, Neve R, Jiang Y . Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer's disease progression. Biol Psychiatry. 2010; 68(10):885-93. PMC: 2965820. DOI: 10.1016/j.biopsych.2010.05.030. View

Perez-Gonzalez R, Gauthier S, Kumar A, Saito M, Saito M, Levy E . A Method for Isolation of Extracellular Vesicles and Characterization of Exosomes from Brain Extracellular Space. Methods Mol Biol. 2016; 1545:139-151. DOI: 10.1007/978-1-4939-6728-5_10. View

Izzo A, Mollo N, Nitti M, Paladino S, Cali G, Genesio R . Mitochondrial dysfunction in down syndrome: molecular mechanisms and therapeutic targets. Mol Med. 2018; 24(1):2. PMC: 6016872. DOI: 10.1186/s10020-018-0004-y. View

Steer E, Dail M, Chu C . Beyond mitophagy: cytosolic PINK1 as a messenger of mitochondrial health. Antioxid Redox Signal. 2015; 22(12):1047-59. PMC: 4390087. DOI: 10.1089/ars.2014.6206. View

Perez-Gonzalez R, Sahoo S, Gauthier S, Kim Y, Li M, Kumar A . Neuroprotection mediated by cystatin C-loaded extracellular vesicles. Sci Rep. 2019; 9(1):11104. PMC: 6668451. DOI: 10.1038/s41598-019-47524-7. View

Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C . Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535(7613):551-5. PMC: 4968589. DOI: 10.1038/nature18928. View

Puhm F, Afonyushkin T, Resch U, Obermayer G, Rohde M, Penz T . Mitochondria Are a Subset of Extracellular Vesicles Released by Activated Monocytes and Induce Type I IFN and TNF Responses in Endothelial Cells. Circ Res. 2019; 125(1):43-52. DOI: 10.1161/CIRCRESAHA.118.314601. View

10.

Perez-Gonzalez R, Gauthier S, Kumar A, Levy E . The exosome secretory pathway transports amyloid precursor protein carboxyl-terminal fragments from the cell into the brain extracellular space. J Biol Chem. 2012; 287(51):43108-15. PMC: 3522305. DOI: 10.1074/jbc.M112.404467. View

11.

Alldred M, Chao H, Lee S, Beilin J, Powers B, Petkova E . Long-term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease. FASEB J. 2019; 33(9):9871-9884. PMC: 6704451. DOI: 10.1096/fj.201802669RR. View

12.

Di Rita A, DAcunzo P, Simula L, Campello S, Strappazzon F, Cecconi F . AMBRA1-Mediated Mitophagy Counteracts Oxidative Stress and Apoptosis Induced by Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells. Front Cell Neurosci. 2018; 12:92. PMC: 5932353. DOI: 10.3389/fncel.2018.00092. View

13.

Haraszti R, Didiot M, Sapp E, Leszyk J, Shaffer S, Rockwell H . High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources. J Extracell Vesicles. 2016; 5:32570. PMC: 5116062. DOI: 10.3402/jev.v5.32570. View

14.

Lin W, Kang U . Characterization of PINK1 processing, stability, and subcellular localization. J Neurochem. 2008; 106(1):464-74. PMC: 3638740. DOI: 10.1111/j.1471-4159.2008.05398.x. View

15.

Phinney D, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix C . Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015; 6:8472. PMC: 4598952. DOI: 10.1038/ncomms9472. View

16.

Kuhlbrandt W . Structure and function of mitochondrial membrane protein complexes. BMC Biol. 2015; 13:89. PMC: 4625866. DOI: 10.1186/s12915-015-0201-x. View

17.

Jiang Y, Mullaney K, Peterhoff C, Che S, Schmidt S, Boyer-Boiteau A . Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition. Proc Natl Acad Sci U S A. 2010; 107(4):1630-5. PMC: 2824382. DOI: 10.1073/pnas.0908953107. View

18.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

19.

Alldred M, Lee S, Petkova E, Ginsberg S . Expression profile analysis of hippocampal CA1 pyramidal neurons in aged Ts65Dn mice, a model of Down syndrome (DS) and Alzheimer's disease (AD). Brain Struct Funct. 2014; 220(5):2983-96. PMC: 4297601. DOI: 10.1007/s00429-014-0839-0. View

20.

Matyash V, Liebisch G, Kurzchalia T, Shevchenko A, Schwudke D . Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J Lipid Res. 2008; 49(5):1137-46. PMC: 2311442. DOI: 10.1194/jlr.D700041-JLR200. View