Autophagy accounts for approximately one-third of mitochondrial protein turnover and is protein selective

Vincow, Evelyn S.; Thomas, Ruth E.; Merrihew, Gennifer E.; Shulman, Nicholas; Bammler, Theo K.; MacDonald, James W.; MacCoss, Michael J.; Pallanck, Leo J.

doi:10.1080/15548627.2019.1586258

Cited by 42 publications

(33 citation statements)

References 113 publications

(151 reference statements)

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“…In cultured mammalian cells, Burman et al (50) demonstrated selective mitophagic clearance of a mutant ornithine transcarbamoylase. Finally, Vincow et al (51,52), using Drosophila, found that mitophagy is protein selective in a whole animal system.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of mitochondrial matrix proteins regulates their selective mitophagic degradation

Kolitsida

Zhou

Rackiewicz

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Mitophagy is an important quality-control mechanism in eukaryotic cells, and defects in mitophagy correlate with aging phenomena and neurodegenerative disorders. It is known that different mitochondrial matrix proteins undergo mitophagy with very different rates but, to date, the mechanism underlying this selectivity at the individual protein level has remained obscure. We now present evidence indicating that protein phosphorylation within the mitochondrial matrix plays a mechanistic role in regulating selective mitophagic degradation in yeast via involvement of the Aup1 mitochondrial protein phosphatase, as well as 2 known matrix-localized protein kinases, Pkp1 and Pkp2. By focusing on a specific matrix phosphoprotein reporter, we also demonstrate that phospho-mimetic and nonphosphorylatable point mutations at known phosphosites in the reporter increased or decreased its tendency to undergo mitophagy. Finally, we show that phosphorylation of the reporter protein is dynamically regulated during mitophagy in an Aup1-dependent manner. Our results indicate that structural determinants on a mitochondrial matrix protein can govern its mitophagic fate, and that protein phosphorylation regulates these determinants.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of mitochondrial matrix proteins regulates their selective mitophagic degradation

Kolitsida

Zhou

Rackiewicz

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…It will also be necessary to assess whether and how MDVs regulate processed peptide efflux from mitochondria. autophagy, suggesting that pathways like MDVs or proteasomal degradation play a significant role in this regard 36 . Here we provide evidence that MDVs are indeed enriched in respiratory chain proteins in a mammalian system.…”

Section: Discussionmentioning

confidence: 99%

Proteomic profiling of mitochondrial-derived vesicles in brain reveals enrichment of respiratory complex sub-assemblies and small TIM chaperones

Roberts

Bayne²,

Goiran

et al. 2020

Preprint

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ABSTRACTThe generation of mitochondrial-derived vesicles (MDVs) is implicated in a plethora of vital cell functions, from mitochondrial quality control to peroxisomal biogenesis. The discovery of distinct subtypes of MDVs has revealed the selective inclusion of mitochondrial cargo in response to varying stimuli. However, the true scope and variety of MDVs is currently unclear, and unbiased approaches have yet to be used to understand their biology. Furthermore, as mitochondrial dysfunction has been implicated in many neurodegenerative diseases, it is essential to understand MDV pathways in the nervous system. To address this, we sought to identify the cargo in brain MDVs. We used an in vitro budding assay and proteomic approach to identify proteins selectively enriched in MDVs. 72 proteins were identified as MDV enriched, of which 31% were OXPHOS proteins. Interestingly, the OXPHOS proteins localized to specific modules of the respiratory complexes, hinting at the inclusion of sub-assemblies in MDVs. Small TIM chaperones were also highly enriched in MDVs, linking mitochondrial chaperone-mediated protein transport to MDV formation. As the two Parkinson’s disease genes PINK1 and Parkin have been previously implicated in MDV biogenesis in response to oxidative stress, we compared the MDV proteomes from the brains of wild-type mice with those of PINK1-/- and Parkin-/- mice. No significant difference was found, suggesting that PINK1- and Parkin-dependent MDVs make up a small proportion of all MDVs in the brain. Our findings demonstrate a previously uncovered landscape of MDV complexity and provide a foundation from which to discover further novel MDV functions.

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“…Piecemeal autophagy of mitochondrial subregions or fragments ( Fig. 2A) may also play a role in extreme cases of protein misfolding, and mitochondria-derived vesicles may directly target outer mitochondrial membrane proteins to lysosomes (16)(17)(18)(19).…”

Section: Quality Control Processes To Cope With Mitochondrial Burdensmentioning

confidence: 99%

Mitochondria—Striking a balance between host and endosymbiont

Youle

2019

Science

152

143

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Mitochondria are organelles with their own genome that arose from α-proteobacteria living within single-celled Archaea more than a billion years ago. This step of endosymbiosis offered tremendous opportunities for energy production and metabolism and allowed the evolution of fungi, plants, and animals. However, less appreciated are the downsides of this endosymbiosis. Coordinating gene expression between the mitochondrial genomes and the nuclear genome is imprecise and can lead to proteotoxic stress. The clonal reproduction of mitochondrial DNA requires workarounds to avoid mutational meltdown. In metazoans that developed innate immune pathways to thwart bacterial and viral infections, mitochondrial components can cross-react with pathogen sensors and invoke inflammation. Here, I focus on the numerous and elegant quality control processes that compensate for or mitigate these challenges of endosymbiosis.

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Autophagy accounts for approximately one-third of mitochondrial protein turnover and is protein selective

Cited by 42 publications

References 113 publications

Phosphorylation of mitochondrial matrix proteins regulates their selective mitophagic degradation

Phosphorylation of mitochondrial matrix proteins regulates their selective mitophagic degradation

Proteomic profiling of mitochondrial-derived vesicles in brain reveals enrichment of respiratory complex sub-assemblies and small TIM chaperones

Mitochondria—Striking a balance between host and endosymbiont

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