Basal mitophagy is widespread in <i>Drosophila</i> but minimally affected by loss of Pink1 or parkin

Lee, Juliette J.; Sánchez-Martínez, Álvaro; Martinez, Aitor; Benincá, Cristiane; Mayor, Ugo; Clague, Michael J.; Whitworth, Alexander J.

doi:10.1083/jcb.201801044

Cited by 277 publications

(302 citation statements)

References 37 publications

Supporting

Mentioning

256

Contrasting

Order By: Relevance

“…We wondered whether, by analogy with the role of USP30 in Parkin-overexpressing cells, this increase in mitophagy was dependent on PINK1. Depleting PINK1 did not affect basal levels of mitophagy, in agreement with two recent reports in mitophagy reporter flies and mice [19,20]. However, PINK1 depletion did suppress the enhancement of mitophagy seen upon USP30 knockdown ( Fig 1D).…”

Section: Enhancement Of Basal Mitophagy By Usp30 Depletion Is Dependesupporting

confidence: 92%

Dual role of USP 30 in controlling basal pexophagy and mitophagy

et al. 2018

Self Cite

View full text Add to dashboard Cite

USP30 is an integral protein of the outer mitochondrial membrane that counteracts PINK1 and Parkin‐dependent mitophagy following acute mitochondrial depolarisation. Here, we use two distinct mitophagy reporter systems to reveal tonic suppression by USP30, of a PINK1‐dependent component of basal mitophagy in cells lacking detectable Parkin. We propose that USP30 acts upstream of PINK1 through modulation of PINK1‐substrate availability and thereby determines the potential for mitophagy initiation. We further show that a fraction of endogenous USP30 is independently targeted to peroxisomes where it regulates basal pexophagy in a PINK1‐ and Parkin‐independent manner. Thus, we reveal a critical role of USP30 in the clearance of the two major sources of ROS in mammalian cells and in the regulation of both a PINK1‐dependent and a PINK1‐independent selective autophagy pathway.

show abstract

Section: Enhancement Of Basal Mitophagy By Usp30 Depletion Is Dependesupporting

confidence: 92%

Dual role of USP 30 in controlling basal pexophagy and mitophagy

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, evidence for the role of the PINK1-Parkin pathway in mitophagy in vivo is limited. Recent studies in mouse and Drosophila showed that basal mitophagy in vivo is PINK1-Parkin pathway independent (37,38). Consistent with these results, we did not observe significant differences in the levels of basal mitophagy in the wing discs of L3 larvae and in dopaminergic neurons of adults after knock down of PINK1 or parkin (unpublished data).…”

Section: Changes In the Mitophagy Level During Drosophila Developmentsupporting

confidence: 91%

“…The role of the PINK1-Parkin pathway in the removal of damaged mitochondria has been well demonstrated in human cell systems (5), but evidence for the role of PINK1 and parkin in mitophagy in vivo is very limited. Several recent studies have shown that loss of PINK1 has no significant effect on mitophagy levels in different tissues (37,38), suggesting that PINK1 function is dispensable for basal mitophagy (45,46). Recently, PINK1 2/2 mice have been shown to be defective in the induction of mitophagy upon exhaustive exercise (14).…”

Section: Discussionmentioning

confidence: 99%

Assessment of mitophagy in mt‐Keima Drosophila revealed an essential role of the PINK1‐Parkin pathway in mitophagy induction in vivo

Kim

Yoon

et al. 2019

FASEB j.

View full text Add to dashboard Cite

Mitophagy has been implicated in mitochondrial quality control and in various human diseases. However, the study of in vivo mitophagy remains limited. We previously explored in vivo mitophagy using a transgenic mouse expressing the mitochondria‐targeted fluorescent protein Keima (mt‐Keima). Here, we generated mt‐Keima Drosophila to extend our efforts to study mitophagy in vivo. A series of experiments confirmed that mitophagy can be faithfully and quantitatively measured in mt‐Keima Drosophila. We also showed that alterations in mitophagy upon environmental and genetic perturbation can be measured in mt‐Keima Drosophila. Analysis of different tissues revealed a variation in basal mitophagy levels in Drosophila tissues. In addition, we found a significant increase in mitophagy levels during Drosophila embryogenesis. Importantly, loss‐of‐function genetic analysis demonstrated that the phosphatase and tensin homolog‐induced putative kinase 1 (PINK1)‐Parkin pathway is essential for the induction of mitophagy in vivo in response to hypoxic exposure and rotenone treatment. These studies showed that the mt‐Keima Drosophila system is a useful tool for understanding the role and molecular mechanism of mitophagy in vivo. In addition, we demonstrated the essential role of the PINK1‐Parkin pathway in mitophagy induction in response to mitochondrial dysfunction.—Kim, Y. Y., Um, J.‐H., Yoon, J.‐H., Kim, H., Lee, D.‐Y., Lee, Y. J., Jee, H. J., Kim, Y. M., Jang, J. S., Jang, Y.‐G., Chung, J., Park, H. T., Finkel, T., Koh, H., Yun, J. Assessment of mitophagy in mt‐Keima Drosophila revealed an essential role of the PINK1‐Parkin pathway in mitophagy induction in vivo. FASEB J. 33, 9742–9751 (2019). http://www.fasebj.org

show abstract

“…Although basal mitophagy has been recently demonstrated to occur in neurons in vivo both in Drosophila and mouse (Cornelissen et al, 2018;Lee et al, 2018;McWilliams et al, 2018), evidence for neuronal mitophagy specifically in response to acute mitochondrial stress remains sparse (Cummins & Götz, 2017;Whitworth & Pallanck, 2017). Consequently, we used C. elegans to test the effect of tau on mitophagy in a live nervous system.…”

Section: Discussionmentioning

confidence: 99%

Disease‐associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria

et al. 2018

View full text Add to dashboard Cite

Accumulation of the protein tau characterises Alzheimer's disease and other tauopathies, including familial forms of frontotemporal dementia (FTD) that carry pathogenic tau mutations. Another hallmark feature of these diseases is the accumulation of dysfunctional mitochondria. Although disease‐associated tau is known to impair several aspects of mitochondrial function, it is still unclear whether it also directly impinges on mitochondrial quality control, specifically Parkin‐dependent mitophagy. Using the mito‐QC mitophagy reporter, we found that both human wild‐type (hTau) and FTD mutant tau (hP301L) inhibited mitophagy in neuroblastoma cells, by reducing mitochondrial translocation of Parkin. In the Caenorhabditis elegans nervous system, hTau expression reduced mitophagy, whereas hP301L expression completely inhibited it. These effects were not due to changes in the mitochondrial membrane potential or the cytoskeleton, as tau specifically impaired Parkin recruitment to defective mitochondria by sequestering it in the cytosol. This sequestration was mediated by aberrant interactions of Parkin with the projection domain of tau. As mitochondria are dysfunctional in neurodegenerative conditions, these data suggest a vicious cycle, with tau also inhibiting the degradation of damaged mitochondria.

show abstract

Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin

Abstract: PINK1/parkin are key mediators of stress-induced mitophagy in vitro, but their impact on basal mitophagy in vivo is unclear. Novel Drosophila reporter lines reveal abundant mitophagy in many tissues, including dopaminergic neurons, that is unaffected by loss of PINK1/parkin.

Cited by 277 publications

References 37 publications

Dual role of USP 30 in controlling basal pexophagy and mitophagy

Dual role of USP 30 in controlling basal pexophagy and mitophagy

Assessment of mitophagy in mt‐Keima Drosophila revealed an essential role of the PINK1‐Parkin pathway in mitophagy induction in vivo

Disease‐associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria

Contact Info

Product

Resources

About