Exposure to a Pathological Condition May Be Required for the Cells to Secrete Exosomes Containing mtDNA Aberration

Abstract

Exosomes, nanovesicles secreted by all cells, carry out intercellular communication by transmitting biologically active cargo comprising DNA, RNA, and proteins. These biomolecules reflect the status of their parent cells and can be altered by pathological conditions. Therefore, the researchers have been investigating differential sequences and quantities of DNA associated with exosomes as valuable biomarkers of diseases. Exosomes carry different types of DNA molecules, including genomic, cytoplasmic, and mitochondrial (mtDNA). The mtDNA aberrations are reported to be a hallmark of diseases involving oxidative stress, such as cancer and neurodegenerative diseases. Establishing robust in vitro models comprising appropriate cell lineages is the first step towards investigating disease-specific anomalies and testing therapeutics. Induced pluripotent stem (iPS) cells from patients with diseases have been used for this purpose since they can differentiate into various cells. The current study investigated mtDNA aberrations in exosomes secreted by primary cancer cells and neural stem cells (NSCs) differentiated from iPS cells. The primary cancer cells were isolated from surgically removed glioblastoma multiforme (GBM) tissue, and the iPS cells were produced from control and Alzheimer’s disease (AD) subjects’ B lymphocytes. We detected aberrations in mtDNA associated with exosomes secreted from GBM cells but not from the NSCs. This result indicates that the cells may not secrete exosomes carrying mtDNA aberration without exposure to a pathological condition. Thus, we may need to consider this fact when we use iPS cell-derived cells as an in vitro disease model.

Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle

“…Exosome transfer is significantly altered under physiological and pathological conditions that can affect the exchanges of mitochondrial materials parallel with mitochondrial dynamic and deformability abilities (Blagov et al, 2022;Liu et al, 2021). Under severe pathological conditions, the loss of homeostasis results in the secretion and production of exosomes devoid of mtDNA (Vaidya et al, 2022).…”

“…Exosome transfer is significantly altered under physiological and pathological conditions that can affect the exchanges of mitochondrial materials parallel with mitochondrial dynamic and deformability abilities (Blagov et al, 2022; Liu et al, 2021). Under severe pathological conditions, the loss of homeostasis results in the secretion and production of exosomes devoid of mtDNA (Vaidya et al, 2022). Using histological and molecular investigations, it was suggested that cardiac resident macrophages can uptake injured mitochondrial particles released by injured cardiomyocytes to maintain basal heart metabolism (Nicolás‐Ávila et al, 2020; Zhang et al, 2023).…”

Mitochondrial SOS: how mtDNA may act as a stress signal in Alzheimer’s disease

“…The opening of this pore has been shown to allow the release of fragments of mtDNA under normal physiological conditions, but under pathological conditions, both the probability of pore opening as well as the amount of mtDNA released from the mitochondria increases significantly [ 17 ]. MtDNA has also been shown to be found in extracellular vesicles released from the cell, and there is some evidence that this process increases under pathological conditions, particularly in neurological disorders [ 18 , 19 ]. As mitochondrial damage and dysfunction increase during states of oxidative stress, mtDNA is also shown to be released upon apoptosis via BAX/BAK signaling and mitochondrial membrane permeabilization [ 20 , 21 ].…”

In utero ethanol exposure induces mitochondrial DNA damage and inhibits mtDNA repair in developing brain

“…Not only mRNA ( Valadi et al, 2007 ; Skog et al, 2008 ; Batagov and Kurochkin, 2013 ), but even double-stranded DNA can be found in exosomes ( Thakur et al, 2014 ; Witwer et al, 2017 ), and exosomes secreted by OLs ( Fruhbeis et al, 2012 ) contain major myelin and stress-protective proteins ( Kramer-Albers et al, 2007 ), lipids ( Skotland et al, 2017 ) and miRNAs ( Ebrahimkhani et al, 2017 ). Recently mtDNA was found in exosomes ( Vaidya et al, 2022 ), which also carry genomic and cytoplasmic DNA. Cells exposed to pathological conditions may secrete exosomes containing abnormal mtDNA ( Vaidya et al, 2022 ), and this might also apply to damage from EtOH exposure.…”

“…Recently mtDNA was found in exosomes ( Vaidya et al, 2022 ), which also carry genomic and cytoplasmic DNA. Cells exposed to pathological conditions may secrete exosomes containing abnormal mtDNA ( Vaidya et al, 2022 ), and this might also apply to damage from EtOH exposure. Considering the previous data ( Darbinian et al, 2021a , 2023 ; Darbinian and Selzer, 2022 ), it would be possible that increased release of soluble factors may be involved in the dysregulation of OL and neuronal growth and survival.…”