COPI-regulated mitochondria-ER contact site formation maintains axonal integrity

Maddison, Daniel C.; Malik, Bilal R.; Amadio, Leonardo; Bis-Brewer, Dana M.; Züchner, Stephan; Peters, Owen M.; Smith, Gaynor A.

doi:10.1016/j.celrep.2023.112883

Cited by 4 publications

(4 citation statements)

References 98 publications

(144 reference statements)

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“…Using Mitocarta 3.0 49 and Uniprot ID Mapping 50 , we determined that 36% of all proteins identified in the somatodendritic compartment and 43% of proteins identified in the axonal compartment are known mitochondrial proteins, making them the most highly represented population in these preparations ( Figure 3B ). Additionally, 10% of somatodendritic and 9% of axonal proteins were identified as ER-localized proteins, as expected from the known physical contacts between ER and mitochondria 44 . It is conceivable that at least some of the other identified proteins may have multiple subcellular localizations or were similarly precipitated due to physical contacts between tagged mitochondria and other cellular structures.…”

Section: Resultsmentioning

confidence: 57%

“…To determine whether purified mitochondria remained intact, we examined the pellets from the immunoprecipitations using transmission electron microscopy and found that the majority of immuno-isolated membranous structures were indeed mitochondria with well-preserved ultrastructure ( Figure 2C ). Additional membranous structures were also observed, likely representing the endoplasmic reticulum, which is known to establish contact sites with mitochondria 44, 45 .…”

Section: Resultsmentioning

confidence: 99%

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Compartmental Differences in the Retinal Ganglion Cell Mitochondrial Proteome

Lewis,

Skiba,

Hao

et al. 2024

Preprint

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Among neurons, retinal ganglion cells (RGCs) are uniquely sensitive to mitochondrial dysfunction. The RGC is highly polarized, with a somatodendritic compartment in the inner retina and an axonal compartment projecting to targets in the brain. The drastically dissimilar functions of these compartments implies that mitochondria face different bioenergetic and other physiological demands. We hypothesized that compartmental differences in mitochondrial biology would be reflected by disparities in mitochondrial protein composition. Here, we describe a protocol to isolate intact mitochondria separately from mouse RGC somatodendritic and axonal compartments by immunoprecipitating labeled mitochondria from RGC MitoTag mice. Using mass spectrometry, 471 and 357 proteins were identified in RGC somatodendritic and axonal mitochondrial immunoprecipitates, respectively. We identified 10 mitochondrial proteins exclusively in the somatodendritic compartment and 19 enriched ≥2-fold there, while 3 proteins were exclusively identified and 18 enriched in the axonal compartment. Our observation of compartment-specific enrichment of mitochondrial proteins was validated through immunofluorescence analysis of the localization and relative abundance of superoxide dismutase (SOD2), sideroflexin-3 (SFXN3) and trifunctional enzyme subunit alpha (HADHA) in retina and optic nerve specimens. The identified compartmental differences in RGC mitochondrial composition may provide promising leads for uncovering physiologically relevant pathways amenable to therapeutic intervention for optic neuropathies.

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Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Compartmental Differences in the Retinal Ganglion Cell Mitochondrial Proteome

Lewis,

Skiba,

Hao

et al. 2024

Preprint

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“…We established a Cdk12 mutant, first made by random mutagenesis in Drosophila using established methods [ 14 – 16 ]. The nature of this mutation was found to be deletion that resulted in a frameshift and premature stop codon.…”

Section: Resultsmentioning

confidence: 99%

Cdk12 maintains the integrity of adult axons by suppressing actin remodeling

Townsend,

Clarke,

Maddison

et al. 2023

Cell Death Discov.

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The role of cyclin-dependent kinases (CDKs) that are ubiquitously expressed in the adult nervous system remains unclear. Cdk12 is enriched in terminally differentiated neurons where its conical role in the cell cycle progression is redundant. We find that in adult neurons Cdk12 acts a negative regulator of actin formation, mitochondrial dynamics and neuronal physiology. Cdk12 maintains the size of the axon at sites proximal to the cell body through the transcription of homeostatic enzymes in the 1-carbon by folate pathway which utilize the amino acid homocysteine. Loss of Cdk12 leads to elevated homocysteine and in turn leads to uncontrolled F-actin formation and axonal swelling. Actin remodeling further induces Drp1-dependent fission of mitochondria and the breakdown of axon-soma filtration barrier allowing soma restricted cargos to enter the axon. We demonstrate that Cdk12 is also an essential gene for long-term neuronal survival and loss of this gene causes age-dependent neurodegeneration. Hyperhomocysteinemia, actin changes, and mitochondrial fragmentation are associated with several neurodegenerative conditions such as Alzheimer’s disease and we provide a candidate molecular pathway to link together such pathological events.

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“…The above results suggest that COPI disruption results in the inhibition of autophagy, which is involved in the mTORC1 pathway. In addition, the COPI vesicle possesses multiple functions, such as Golgi–ER trafficking [ 43 ], mitochondria–ER contact site formation [ 47 ], reactive oxygen production [ 48 ], and cell differentiation [ 49 ]. It has been reported that mitochondria–endoplasmic reticulum contact sites are involved in the formation of autophagosomes [ 50 ], which need further exploration.…”

Section: Discussionmentioning

confidence: 99%

COPI Vesicle Disruption Inhibits Mineralization via mTORC1-Mediated Autophagy

Nie,

Ma,

Zhang

et al. 2023

IJMS

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Bone mineralization is a sophisticated regulated process composed of crystalline calcium phosphate and collagen fibril. Autophagy, an evolutionarily conserved degradation system, whereby double-membrane vesicles deliver intracellular macromolecules and organelles to lysosomes for degradation, has recently been shown to play an essential role in mineralization. However, the formation of autophagosomes in mineralization remains to be determined. Here, we show that Coat Protein Complex I (COPI), responsible for Golgi-to-ER transport, plays a pivotal role in autophagosome formation in mineralization. COPI vesicles were increased after osteoinduction, and COPI vesicle disruption impaired osteogenesis. Mechanistically, COPI regulates autophagy activity via the mTOR complex 1 (mTORC1) pathway, a key regulator of autophagy. Inhibition of mTOR1 rescues the impaired osteogenesis by activating autophagy. Collectively, our study highlights the functional importance of COPI in mineralization and identifies COPI as a potential therapeutic target for treating bone-related diseases.

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COPI-regulated mitochondria-ER contact site formation maintains axonal integrity

Cited by 4 publications

References 98 publications

Compartmental Differences in the Retinal Ganglion Cell Mitochondrial Proteome

Compartmental Differences in the Retinal Ganglion Cell Mitochondrial Proteome

Cdk12 maintains the integrity of adult axons by suppressing actin remodeling

COPI Vesicle Disruption Inhibits Mineralization via mTORC1-Mediated Autophagy

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