Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired, 2023, Liang et al.

[SNT Gatchaman]

Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired
Liang, Wenjing; Sagar, Shakti; Ravindran, Rishith; Najor, Rita H.; Quiles, Justin M.; Chi, Liguo; Diao, Rachel Y.; Woodall, Benjamin P.; Leon, Leonardo J.; Zumaya, Erika; Duran, Jason; Cauvi, David M.; De Maio, Antonio; Adler, Eric D.; Gustafsson, Åsa B.

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.

Link | PDF (Nature Communications)

 

[SNT Gatchaman]

Mitochondria play a central role in cardiac energy metabolism and are responsible for generating most of the energy needed to sustain contraction. Because cardiac myocytes are post-mitotic, maintaining a healthy population of mitochondria is essential for their long-term survival. Intracellular degradation pathways that are responsible for eliminating defective and potentially harmful mitochondria rely on lysosomes for the breakdown of cargo. In this study, we identified an alternative pathway for elimination of mitochondria and ubiquitinated proteins from cells when lysosomal function is compromised that involves their secretion in large EVs.

This study observed that mitochondria sequested in autophagosomes are transported to the plasma membrane, where they are released by outward budding of the plasma membrane. Recent studies have reported that lysosomal inhibition can activate secretory autophagy to clear autophagic cargo and mitochondria from cells.

Here, we found that mitochondria and p62 can be secreted independently of Atg5 and Atg7 in vesicles that are similar to small EVs (i.e. exosomes), an indication that these vesicles originate from the same endosomal pathway. Our finding that disrupting autophagosome formation alone failed to increase EV secretion at baseline also suggests that alternative internal clearance pathways are compensating and delivering cargo to lysosomes for degradation. It also suggests that the EV secretion pathway is linked to lysosomal function and is primarily utilized when lysosomal function is compromised or overwhelmed.

It is well established that EVs can function as signaling vesicles by delivering nucleotides and proteins to other cells. Uptake of encapsulated mitochondria has also been reported to influence cellular function after uptake. For instance, microvesicles enriched in mitochondria released by monocytic cells are pro-inflammatory and induce type I Interferons (IFN) and Tumor necrosis factor (TNF) signaling in endothelial cells after uptake, whereas mitochondria phagocytosed by macrophages undergo fusion with the existing mitochondrial network and enhance respiration.

 

[SNT Gatchaman]

Is there then a possibility of —

Damaged mitochondria being shared around due to impaired mitophagy —> induction of more bad mitochondria (and impaired autophagy) in more cells ?