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Cited by 273Extracellular vesicles in diseaseAutophagy in Disease and TherapyCellular transport and secretion

Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired

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Liang, Wenjing, Sagar, Shakti, Ravindran, Rishith, Najor, Rita H., Quiles, Justin M., Chi, Liguo, Diao, Rachel Y., Woodall, Benjamin P. +7 more·2023·Nature Communications
DOI 10.1038/s41467-023-40680-5PMC PMC10439183
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Abstract

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.

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  • Mitochondrial intercellular transfer plays a crucial role in the maintenance of mitochondrial homeostasis.

    “Recent evidence suggests that mitochondrial intercellular transfer also plays a crucial role in the maintenance of mitochondrial homeostasis [7, 8].”

    From Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease (2025) · cites this paper as [7]

    The Results section reports that mitochondria released from adult mouse heart cells are taken up by macrophages and that this response is sufficient to maintain cardiac homeostasis during autophagy dysfunction. The Discussion describes this as an alternative quality-control pathway when lysosomal degradation is impaired. These passages support a role for intercellular mitochondrial transfer in homeostasis, but not the broader claim that it is generally crucial for maintaining mitochondrial homeostasis. (LLM, conf=0.84)

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Cited by

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Authors
Liang, W., Sagar, S., Ravindran, R., Najor, R. H., Quiles, J. M., Chi, L., Diao, R. Y., Woodall, B. P., Leon, L. J., Zumaya, E., Duran, J., Cauvi, D. M., De Maio, A., Adler, E. D., & Gustafsson, Å. B.
Affiliations
University of California San Diego (US)
Corresponding author
Gustafsson, Åsa B.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-08-18
Volume
14
Issue
1
Pages
5031-5031
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-40680-5
PMC
PMC10439183
OpenAlex
W4385971551
Cited by
273
References
6
Citations by year
2026: 95 · 2025: 93 · 2024: 71 · 2023: 11 · 2022: 2
FWCI
23.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Tobacco-Related Disease Research Program (T30FT0846)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
extracellular vesicles, lysosomal dysfunction, mitochondrial quality control, Rab7, multivesicular bodies, endocytic pathway, macrophage uptake, Danon disease, cardiac aging, heart

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