Loss of the Drosophila m-AAA mitochondrial protease paraplegin results in mitochondrial dysfunction, shortened lifespan, and neuronal and muscular degeneration

Pareek, Gautam; Thomas, Ruth E.; Pallanck, Leo J.

doi:10.1038/s41419-018-0365-8

Cited by 31 publications

(31 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1b ). The maximal and median lifespans of Lon KD flies were similar to those of flies bearing null mutations in genes encoding the other AAA + mitochondrial protease family members dYME1L and SPG7 25 , 26 . Young Lon KD flies also exhibited defects in climbing and flight starting early in life (Fig.…”

Section: Resultsmentioning

confidence: 68%

“…The Lon knockout allele was created using CRISPR/Cas9-mediated gene editing according to a published procedure 25 , 57 . Briefly, we replaced the Lon (CG8798) coding sequence with DsRed through homology-mediated repair.…”

Section: Methodsmentioning

confidence: 99%

“…Mitochondrial respiratory chain activity assays were performed according to a published procedure with several minor modifications 25 . Briefly, 1000 adult flies were homogenized in isolation buffer (5 mM Tris (pH 7.4), 250 mM sucrose, and 2 mM EGTA) with 1% (w/v) fatty acid free bovine serum albumin.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Lon protease inactivation in Drosophila causes unfolded protein stress and inhibition of mitochondrial translation

et al. 2018

Self Cite

View full text Add to dashboard Cite

Mitochondrial dysfunction is a frequent participant in common diseases and a principal suspect in aging. To combat mitochondrial dysfunction, eukaryotes have evolved a large repertoire of quality control mechanisms. One such mechanism involves the selective degradation of damaged or misfolded mitochondrial proteins by mitochondrial resident proteases, including proteases of the ATPase Associated with diverse cellular Activities (AAA+) family. The importance of the AAA+ family of mitochondrial proteases is exemplified by the fact that mutations that impair their functions cause a variety of human diseases, yet our knowledge of the cellular responses to their inactivation is limited. To address this matter, we created and characterized flies with complete or partial inactivation of the Drosophila matrix-localized AAA+ protease Lon. We found that a Lon null allele confers early larval lethality and that severely reducing Lon expression using RNAi results in shortened lifespan, locomotor impairment, and respiratory defects specific to respiratory chain complexes that contain mitochondrially encoded subunits. The respiratory chain defects of Lon knockdown (LonKD) flies appeared to result from severely reduced translation of mitochondrially encoded genes. This translational defect was not a consequence of reduced mitochondrial transcription, as evidenced by the fact that mitochondrial transcripts were elevated in abundance in LonKD flies. Rather, the translational defect of LonKD flies appeared to be derived from sequestration of mitochondrially encoded transcripts in highly dense ribonucleoparticles. The translational defect of LonKD flies was also accompanied by a substantial increase in unfolded mitochondrial proteins. Together, our findings suggest that the accumulation of unfolded mitochondrial proteins triggers a stress response that culminates in the inhibition of mitochondrial translation. Our work provides a foundation to explore the underlying molecular mechanisms.

show abstract

Section: Resultsmentioning

confidence: 68%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Lon protease inactivation in Drosophila causes unfolded protein stress and inhibition of mitochondrial translation

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…The m-AAA protease exposes its catalytic domain to the matrix, while the catalytic domain of the i-AAA protease faces the intermembrane space. These proteases degrade misfolded proteins of the inner membrane, being their substrate specificity mainly depending on the topology of the respective substrates (Leonhard et al, 2000;Almajan et al, 2012;Stiburek et al, 2012;Anand et al, 2014;Kondadi et al, 2014;König et al, 2016;Wai et al, 2016;Wang et al, 2016;Pareek et al, 2018;Sprenger et al, 2019). In the inner mitochondrial membrane space, misfolded and damaged proteins are degraded by the proteases Omi/HtrA2 and Atp23 (Osman et al, 2007;Clausen et al, 2011).…”

Section: Mitochondrial Proteolytic Machinerymentioning

confidence: 99%

Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

Escobar-Henriques¹,

Altin²,

Brave³

2020

Current Issues in Molecular Biology

View full text Add to dashboard Cite

Eukaryotic cells are subdivided into membranebound compartments specialized in different cellular functions and requiring dedicated sets of proteins. Although cells developed compartmentspecific mechanisms for protein quality control, chaperones and ubiquitin are generally required for maintaining cellular proteostasis. Proteotoxic stress is signalled from one compartment into another to adjust the cellular stress response. Moreover, transport of misfolded proteins between different compartments can buffer local defects in protein quality control. Mitochondria are special organelles in that they possess an own expression, folding and proteolytic machinery, of bacterial origin, which do not have ubiquitin. Nevertheless, the importance of extensive crosstalk between mitochondria and other subcellular compartments is increasingly clear. Here, we will present local quality control mechanisms and discuss how cellular proteostasis is affected by the interplay between mitochondria and the ubiquitin proteasome system.

show abstract

“…Therefore, the stability of synaptic boutons is a dynamic balance among growth [12], pruning, degeneration, and elimination processes. Synapse degeneration is a complicated process that includes retraction [18,19] and degradation [14,20] of presynaptic and postsynaptic components, such as synaptic vesicles [13,15,19,[21][22][23], microtubules [2], and postsynaptic PSD [24]. Disordered elimination after synaptic degeneration can lead to autism [25] and other neurological diseases.…”

Section: Page 3/35mentioning

confidence: 99%

Neurexin and Neuroligins Jointly Regulate Synaptic Degeneration at the Drosophila Neuromuscular Junction based on TEM Studies

G¹,

Chenchen²,

Xiang³

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract Background: The Drosophila larval neuromuscular junction (NMJ) is a well-known model system and is often used to study synapse development and signal transmission in neurology. Here, we show the synaptic degeneration at NMJ boutons, primarily based on transmission electron microscopy (TEM) studies.Methods: To this aim, we extensively acquire the ultrastructure of diffuse NMJ boutons using continuous sectioning and transmission electron microscope in the wide type and the dneurexin (dnrx) and dneuroligins (dngs) mutant.Results: When degeneration starts, the subsynaptic reticulum (SSR) swells, retracts and folds inward, and then, the residual SSR degenerates into a disordered, thin or linear membrane with a shrinking postsynaptic area (PSA) and axon terminal. The axon terminal begins to degenerate from the central region, and the T-bar structure detaches from the presynaptic membrane with clustered synaptic vesicles to accelerate large-scale degeneration, accompanied by retraction of synaptic vesicles and mitochondria. There are two degeneration modes for clear synaptic vesicles. In the first mode, synaptic vesicles without actin filaments degenerate on the membrane with ultrafine spots and collapse and disperse to form an irregular profile with dark ultrafine particles. In the second mode, clear synaptic vesicles with actin filaments degenerate into dense synaptic vesicles, form irregular dark clumps without a membrane, and collapse and disperse to form an irregular profile with dark ultrafine particles. Last, all residual membranes in NMJ boutons, including presynaptic and postsynaptic membranes, become very thin, most of the SSR degenerates into a linear shape, and all the residual elements in axon terminals, such as synaptic vesicles, mitochondria, the cytoskeleton, and the T-bar, degenerate in situ and eventually form a cluster of dark ultrafine particles. Axon terminals and elements within axon terminals degenerate with the postsynaptic SSR, and swelling and retraction of the SSR occurs prior to axon terminal degradation, which degenerates faster and with more intensity than the SSR. NMJ bouton degeneration occurs under normal physiological conditions, but degeneration in dnrx and dnlgs mutant is accelerated. Furthermore, there is a synergistic effect in dnrx;dnlgs double mutants and dnlg2;dnlg3 double mutants that promotes degeneration of NMJ boutons.Conclusions: NMJ bouton degeneration occurs under normal physiological conditions but is accelerated in dnrx and dnlgs mutants. Furthermore, there is a synergistic effect in dnrx;dnlgs double mutants and dnlg2;dnlg3 double mutants that promotes degeneration of NMJ boutons, which suggests that both neurexin and neuroligins play a vital role in preventing synaptic degeneration. This study proposes the model of NMJ bouton degeneration patterns, which is very conducive to in-depth study of neurodegeneration.

show abstract

Loss of the Drosophila m-AAA mitochondrial protease paraplegin results in mitochondrial dysfunction, shortened lifespan, and neuronal and muscular degeneration

Cited by 31 publications

References 62 publications

Lon protease inactivation in Drosophila causes unfolded protein stress and inhibition of mitochondrial translation

Lon protease inactivation in Drosophila causes unfolded protein stress and inhibition of mitochondrial translation

Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

Neurexin and Neuroligins Jointly Regulate Synaptic Degeneration at the Drosophila Neuromuscular Junction based on TEM Studies

Contact Info

Product

Resources

About