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PINK1 and parkin shape the organism-wide distribution of a deleterious mitochondrial genome

Arnaud Ahier, Nadia Cummins, Chuan-Yang Dai, Jürgen Götz , Steven Zuryn

Posted on: 1 July 2020 , updated on: 5 July 2020

Preprint posted on 12 June 2020

Article now published in Cell Reports at http://dx.doi.org/10.1016/j.celrep.2021.109203

How to be an “elegans” Frankenstein: mitophagy controls mtDNA mosaicism in worms.

Selected by Andrea Irazoki

Categories: cell biology, genetics

BACKGROUND

Besides being the powerhouses of the cell, mitochondria are also responsible for a number of other cellular processes, including macromolecule synthesis, calcium storage and handling, apoptosis, immunity and redox balance [1]. Due to their  α-proteobacterial ancestry, mitochondria hold their own genome, known as mitochondrial DNA (mtDNA) which encodes for 13 proteins. These proteins are mainly involved in mtDNA transcription, translation and oxidative phosphorylation. In fact, mutations in mitochondria-encoded genes are associated to devastating conditions, including myopathies or peripheral neuropathies [2]. Besides, the level of heteroplasmy (presence of non-identical mtDNA copies within a cell) of pathogenic mtDNA mutations not only leads to their mosaic distribution across the organism, but it also correlates with the severity of the clinical phenotypes [3], which highlights the relevance of heteroplasmy and mosaicism in the pathophysiology of mitochondrial disorders. Furthermore, it has been observed that differences in heteroplasmy between tissues are rather deterministic, however, the mechanisms that govern mtDNA heteroplasmy and mosaicism are unknown. In their preprint, Ahier et al. unravel a role for mitochondrial selective autophagy (mitophagy) in the removal of mutated mitochondrial genes in major somatic tissue groups of C. elegans, equalising heteroplasmy across the entire organism. Mechanistically, the authors propose that the mitophagy proteins PINK1 and PDR-1 (parkin) allow the selective clearance of mutated mtDNA in some tissues (neurons, intestinal and epidermal cells) more than in others (body wall muscle cells) and that neurons are more susceptible to increases in heteroplasmy upon overexpression of proteotoxic species related to neurodegenerative disorders.

 

KEY FINDINGS

Using a strain of C. elegans that contains a stable 3.1kb deletion (ΔmtDNA) in its mitochondrial genome, Ahier et al. assessed the role of mitophagy in the control of heteroplasmy of different tissues within worms. In fact, they introduced the ΔmtDNA mutation into strains containing null mutations for both Pink1 and PDR1 (parkin), which are responsible for targeting depolarized, and, therefore, defective mitochondria to the autophagic machinery. In order to facilitate the isolation of mitochondria from different tissues, they introduced a mitochondrial tag under the control of either tissue-specific promoters, such as body wall muscle, intestine, neurons and epidermis, or an ubiquitous promoter.

This approach revealed that relative ΔmtDNA levels differ in neurons, body wall muscle cells, intestinal or epidermal cells, with body wall muscle cells being the ones with the highest levels of heteroplasmy. However, ablation of Pink1 and PDR1 abolished these differences without altering mtDNA copy number, suggesting that these proteins are responsible for setting stereotyped patterns of heteroplasmy in worms. When comparing individual tissues, ablation of these proteins increased heteroplasmy in all assessed tissues, except for body wall muscle cells, which suggests that the role of Pink1 and PDR1 in controlling heteroplasmy is cell type-specific.  Furthermore, the authors demonstrate that differences in the intrinsic mitochondrial physiology between neurons and body wall cells, which carry the lowest and the highest mutation loads, respectively, do not contribute to their differences in heteroplasmy, which are indeed determined by their Pink1 and PDR-1 activities.

Next, the authors hypothesized that mitophagy itself may respond differently to the presence of ΔmtDNA in each cell type. To assess that, they quantified the overlap percentage of mitochondria and autophagosomes by immunostaining in the nervous system and body wall muscles. The results inferred that ΔmtDNA induces mitophagy in both tissues, although mitophagy induction was greater in neurons than in body wall muscle cells, which would explain two of their observations: first, that neurons present lower heteroplasmy levels compared to body wall muscle cells and second, that ablation of Pink1 and PDR1 in neurons has a larger effect on heteroplasmy in neurons. These results were corroborated by altering mitophagy by other physiological conditions, such as the accumulation of proteotoxic species in the nervous system. The accumulation of proteotoxic tau in neurons, which is known to drive Alzheimer’s disease, as well as the accumulation of other proteotoxic species, increased ΔmtDNA levels. These data suggest that the molecular trigger of a broad range of neurodegenerative disorders, i.e. the formation of proteotoxic aggregates, inhibits mitophagy and allows accumulation of ΔmtDNA mutations in neurons, which could be contributing to the development of the disease.

 

WHY I CHOSE THIS PREPRINT

A high number of mitochondrial diseases are caused by mutations in the mitochondrial genome. These mutations can be either inherited by the progenitors or the result of mistakes produced during mtDNA transcription and/or reparation. Either way, cells cope with the accumulation of mutated mtDNA copies by promoting selective mitochondrial removal. However, the mechanisms that govern such processes are unknown. The authors of the highlighted preprint propose a role for the mitophagic proteins Pink1 and PDR1 (Parkin) in the control of the levels of heteroplasmy in an elegant and simple manner. Besides, they confirm the fact that tissue specificity impacts on the level of mosaicism within the different tissues of an organism, and this can be key in the amelioration of the clinical phenotypes of mitochondrial disorders.

 

MY QUESTIONS TO THE AUTHORS

  1. Do you consider that other mitophagic proteins can also be playing a similar role than Pink1/PDR1 in the control of heteroplasmy?
  2. The Pink1/PDR1 mitophagy pathway is subjected to mitochondrial membrane depolarization. Have you assessed whether these proteins undergo the same role in the regulation of heteroplasmy in conditions where there is no mitochondrial membrane depolarization? If not, what do you speculate?
  3. Would you suggest that targeting ΔmtDNA removal through mitophagy could be a feasible treatment for neurodegenerative disorders characterized by accumulation of proteotoxic species?

 

REFERENCES

[1] Nunnari J. and Suomalainen A. (2012). “Mitochondria: In Sickness and in Health.” Cell 148(6): 1145–59.

[2] Taylor R.W. and Turnbull D.M. (2007) “Mitochondrial DNA mutations in Human Disease.” Nature Reviews Genetics 6(5): 389–402.

[3] Hahn A. and Zuryn S. (2019) “The Cellular Mitochondrial Genome Landscape in Disease.” Trends Cell Biol 29: 227-240

 

 

doi: https://doi.org/10.1242/prelights.22532

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Author's response to the proposed questions

Arnaud Ahier and Steven Zuryn shared

1. Do you consider that other mitophagic proteins can also be playing a similar role than Pink1/PDR1 in the control of heteroplasmy?

This is certainly possible. It is interesting however, that removal of both pink-1 and pdr-1 genes is sufficient to equalise ∆mtDNA heteroplasmy levels across the tissue types studied. This suggests that these genes are major contributors, but does not rule out that other cell types, not studied here, use alternative factors.

 

2. The Pink1/PDR1 mitophagy pathway is subjected to mitochondrial membrane depolarization. Have you assessed whether these proteins undergo the same role in the regulation of heteroplasmy in conditions where there is no mitochondrial membrane depolarization? If not, what do you speculate?

This is an interesting question that we have not yet addressed. It is likely that if a mtDNA mutation does not lead to mitochondrial depolarization, it will neither activate nor be under the selection of mitophagy. Whether other cellular processes can detect and remove mtDNA mutations that do not depolarize mitochondria are yet to be found. It is also possible that this mutation may not be deleterious for mitochondrial function and may therefore not warrant selective removal in the first instance. There are natural variations in the mtDNA sequence between human populations that may have developed in this manner.

 

3. Would you suggest that targeting ΔmtDNA removal through mitophagy could be a feasible treatment for neurodegenerative disorders characterized by accumulation of proteotoxic species?

This is indeed a possibility that we think deserves greater scrutiny. Determining whether the build up of mtDNA mutations in neurons causes or contributes to neurodegenerative disease requires further evidence at this stage. If true, then enhancing the ability of cellular pathways, such as mitophagy, to selectively remove these mutations would be a therapeutic avenue worth pursuing.

 

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