Alternative mitochondrial quality control mediated by extracellular release

Abstract

Mitochondrial quality control, which is crucial for maintaining cellular homeostasis, has been considered to be achieved exclusively through mitophagy. Here we report an alternative mitochondrial quality control pathway mediated by extracellular mitochondria release. By performing time-lapse confocal imaging on a stable cell line with fluorescent-labeled mitochondria, we observed release of mitochondria from cells into the extracellular space. Correlative light-electron microscopy revealed that majority of the extracellular mitochondria are in free form and, on rare occasions, some are enclosed in membrane-surrounded vesicles. Rotenone-and carbonyl cyanide m-chlorophenylhydrazone-induced mitochondrial quality impairment promotes the extracellular release of depolarized mitochondria. Overexpression of PRKN (parkin RBR E3 ubiquitin protein ligase), which has a pivotal role in mitophagy regulation, suppresses the extracellular mitochondria release under basal and stress condition, whereas its knockdown exacerbates it. Correspondingly, overexpression of PRKNindependent mitophagy regulators, BNIP3 (BCL2 interacting protein 3) and BNIP3L/NIX (BCL2 interacting protein 3 like), suppress extracellular mitochondria release. Autophagy-deficient cell lines show elevated extracellular mitochondria release. These results imply that perturbation of mitophagy pathway prompts mitochondria expulsion. Presence of mitochondrial protein can also be detected in mouse sera. Sera of PRKN-deficient mice contain higher level of mitochondrial protein compared to that of wild-type mice. More importantly, fibroblasts and cerebrospinal fluid samples from Parkinson disease patients carrying loss-of-function PRKN mutations show increased extracellular mitochondria compared to control subjects, providing evidence in a clinical context. Taken together, our findings suggest that extracellular mitochondria release is a comparable yet distinct quality control pathway from conventional mitophagy.

Extracellular Mitochondrial Components and Effects on Cardiovascular Disease

“…Clearance of depolarized mitochondria under mitochondrial stress has emerged as an alternative mitochondrial quality control pathway. Mitochondria released into extracellular space are predominantly in free form (500 nm-1.5 mm) rather than in membrane-surrounded vesicles (Choong et al, 2020). This finding is consistent with the previous research that free mitochondria and mitoparticles derived from astrocyte spanned a range of sizes from 300 to 1100 nm (Hayakawa et al, 2016).…”

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

“…In addition to mitophagy and MDVs, another recently described neuronal mitochondrial quality control mechanism that may be relevant to peripheral neuropathy is the release of axonal mitochondria into the extracellular space. Such mitochondrial expulsion has been described in the mammalian CNS [352], in C. elegans neurons [353], and has been observed in the context of stresses that damage mitochondria where it appears to complement mitophagy as a quality control mechanism [354]. Furthermore, in retinal ganglion cell axons, and likely throughout the CNS, these released mitochondria can be taken up by astrocytes where they can then be degraded in a process termed transmitophagy [352].…”

Resveratrol enhanced mitochondrial recovery from cryopreservation‐induced damages in oocytes and embryos

“…Recently, Choong et al reported that CH12 cells secrete mitochondria into the culture medium, and the extent of the mitochondrial secretion increased upon treatment of the cells with CCCP or by suppression of PRKN and BNIP3 expression; however, the secretion was decreased by overexpression of PRKN and BNIP3, and it was concluded that the release of mitochondria into the culture medium is a distinct mitochondrial quality control pathway. 64 In this context, resveratrol increased mitochondrial cell‐free DNA in the culture medium of cryopreserved‐warmed embryos and concomitantly, decreased mitochondrial DNA copy number and protein levels in the embryos. 10 , 11 …”