The Potential Use of Mitochondrial Extracellular Vesicles as Biomarkers or Therapeutical Tools

Abstract

The mitochondria play a crucial role in cellular metabolism, reactive oxygen species (ROS) production, and apoptosis. Aberrant mitochondria can cause severe damage to the cells, which have established a tight quality control for the mitochondria. This process avoids the accumulation of damaged mitochondria and can lead to the release of mitochondrial constituents to the extracellular milieu through mitochondrial extracellular vesicles (MitoEVs). These MitoEVs carry mtDNA, rRNA, tRNA, and protein complexes of the respiratory chain, and the largest MitoEVs can even transport whole mitochondria. Macrophages ultimately engulf these MitoEVs to undergo outsourced mitophagy. Recently, it has been reported that MitoEVs can also contain healthy mitochondria, whose function seems to be the rescue of stressed cells by restoring the loss of mitochondrial function. This mitochondrial transfer has opened the field of their use as potential disease biomarkers and therapeutic tools. This review describes this new EVs-mediated transfer of the mitochondria and the current application of MitoEVs in the clinical environment.

Keywords: MitoEVs; biomarker; extracellular vesicles; mitochondria; therapy.

Figure 1

Mitochondria quality control and MitoEVs formation. Aberrant mitochondrial components can be degraded by the UPS, but also be incorporated in MDV that fuse with lysosomes to form MVB, leading to the formation and delivery of small mitoEVs. Whole damaged mitochondria are subjected to fusion and fission processes, the latter ending in mitophagy and promoting transmitophagy through the formation and release of large mitoEVs. UPS: Ubiquitin proteasome system; MDV: mitochondria-derived vesicles; MVBs: multivesicular bodies; PINK1: PTEN-induced putative protein kinase 1; MVB: multivesicular bodies; EVs: extracellular vesicles; Mfn1: mitofusin 1; Mfn2: mitofusin 2; Opa1: optic atrophy 1; Drp-1: dynamin-related protein 1; FIS1: mitochondrial fission protein 1; LC3: microtubule-associated protein 1 light chain 3.

Figure 2

Graphical explanation of the potential therapeutic and diagnostic use of large and small MitoEVs. Larger MitoEVs refer to EVs that are shed from the plasmatic membrane of the cell and can include whole mitochondria; these EVs are particularly interesting in the field of mitochondrial transfer as therapeutic vehicles. Small MitoEVs are included in MVB previous to their release and contain material from the mitochondrial origin (mtDNA and proteins); its analysis may serve as a diagnostic tool in liquid biopsies.