Cells Can Eject Damaged Mitochondria

A sizable fraction of cell signaling is carried in extracellular vesicles, membrane-wrapped packages of molecules. In the course of investigating cell signaling, researchers have noted that some fraction of these vesicles are in fact mitochondria. Cells can readily ingest mitochondria, just as they do other vesicles, and put the mitochondria to work. Mitochondria are organelles descended from ancient symbiotic bacteria, primarily responsible for generating chemical energy store molecules to power cell processes, but also deeply integrated into a wide range of cellular mechanisms beyond this. Mitochondria have their own DNA, replicate like bacteria, and are cleared when damaged by the quality control mechanisms of mitophagy, a form of autophagy that delivers mitochondria to a lysosome where they are broken down. With aging, mitochondria become dysfunctional, and this dysfunction is thought to be important in aging.

The popular science article noted here reports on the discovery that cells in aged tissues can eject damaged mitochondria instead of recycling them. In this case the mitochondria are encapsulated into a vesicle rather than released as-is. The interesting question is what this might do to surrounding cells if they fail to direct these mitochondria to their lysosomes. To what degree can a dysfunctional cell cause harm by shipping out damaged mitochondria for other cells to ingest and react to? One thought is that while the general malaise in mitochondrial function in tissues throughout the body appears to stem from widespread changes in the expression of important nuclear genes, rare cases of severe damage to mitochondrial DNA can produce mitochondria that are both dysfunctional and capable of replicating more effectively than their functional peers, taking over the cell. Can that problem be exported from a dysfunctional cell to a functional cell, and how often does that occur?

The most interesting of strategies to address mitochondrial dysfunction with aging are (a) partial reprogramming, attempting to recreate the processes of early embryonic development that reset mitochondrial function, and (b) transplantation of large numbers of functional mitochondria harvested from cell cultures. The latter is more likely to become a viable, readily available therapy in the near future, as many clinics already work with harvested extracellular vesicles. In principle it should little matter whether and to what degree cells spread mitochondrial dysfunction given a cost-effective treatment that supplies new mitochondria to a sizable fraction of cells in a tissue.

Taking Out the Trash: An Alternative Cellular Disposal Pathway

Organelle health is vital to a cell's function. Consequently, cells have many mechanisms to repair or eliminate defective organelles. In a recent paper, researchers determined that cardiac myocytes and other cells use secretion to remove mitochondria from the cell when lysosomal degradation is inhibited. Mitochondria generate most of the cell's energy. However, when they become dysfunctional, damaged, or old, mitochondria can turn into pro-death organelles, which produce reactive oxygen species that damage the cell's proteins and DNA. This is a major problem for cardiac myocytes, which rely on the energy produced by mitochondria to contract. Additionally, the body cannot replace these particular cells because they do not divide.

Cells have various quality control mechanisms to detect and repair dysfunctional mitochondria, but when the organelles are too damaged, the cell degrades them using lysosomes. We wanted to determine what happens to the cell when the lysosomes are not functioning well or are overwhelmed, and if there was another pathway to temporarily deal with the damaged mitochondria. This information is of particular importance to patients with Danon's disease, who have mutations in a lysosomal protein that causes cardiomyopathy.

We discovered that fibroblasts and cardiac myocytes secrete mitochondria inside extracellular vesicles (EV) when their lysosomal function is compromised or overwhelmed. This encapsulation ensures that the mitochondria do not elicit a dangerous immune response once outside the cell because of their bacterial origin. The mitochondria-containing EV originate from within multivesicular bodies (MVB), which either deliver the cargo to the lysosomes for degradation or ship everything to the plasma membrane for secretion. We found that Rab7, a protein present on the MVB's outer membrane, is a regulator involved in dictating the fate of the vesicles. We believe that active Rab7 directs the EV toward the lysosomes, but in the absence of this protein or when it is inactive, the cell will traffic the EV to the plasma membrane.

Once cardiac myocytes release the mitochondria-containing EV, resident cardiac macrophages and other cells in the heart internalize the vesicles to degrade them through their lysosomes. The EV do not seem to enter circulation but stay within the heart. Ultimately, this is an alternative garbage disposal pathway used by cells to get rid of dysfunctional and damaged mitochondria when they cannot degrade the organelles in their own lysosomes.

Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired

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.

Comments

3rd Stage Sleep Cycle for healthy individuals triggers brain clearance of waste. This scientific conclusion now is well proven. During this 3rd wave cycle of sleep, if damaged Mitocondrial is ejected from the Brain and the Heart, where there is sizable presence of mitocondria, an experiment can be designed to detect such.?

Posted by: Avi Dey at June 23rd, 2024 6:42 AM
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