LONP1 and mtHSP70 cooperate to promote mitochondrial protein folding

Shin, Chun-Shik; Meng, Shuxia; Garbis, Spiros D.; Moradian, Annie; Taylor, Robert W.; Sweredoski, Michael J.; Lomenick, Brett; Chan, David C.

doi:10.1038/s41467-020-20597-z

Cited by 73 publications

(66 citation statements)

References 37 publications

(47 reference statements)

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“…As a consequence, rpl-7 RNAi reduces the burden of insoluble proteins and crowding effects in the nucleus/nucleolus (Vecchi et al, 2020), which results in an increased lifespan. In contrast to RPL-7, HSP-6 is a chaperone and part of the protein folding system of the organism (Ruan et al, 2020; Shin et al, 2021). HSP-6 is the mitochondrial HSP-70, highly conserved, and has the ability to prevent aggregation (Bender et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Pollutants corrupt resilience pathways of aging in the nematode C. elegans

Scharf

Limke

Guehrs

et al. 2021

Preprint

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Delaying aging while prolonging health and lifespan is a major goal in aging research. While many resources have been allocated to find positive interventions with promising results, negative interventions such as pollution and their accelerating effect on age-related degeneration and disease have been mostly neglected. Here, we used the short-lived model organism C. elegans to analyze whether two candidate pollutants interfere with positive interventions by corrupting general aging pathways. We took advantage of the immense data sets describing the age-related remodeling of the proteome including increased protein insolubilities to complement our analysis. We show that the emergent pollutant silica nanoparticles (NP) and the classic xenobiotic inorganic mercury reduce lifespan and cause a premature protein aggregation phenotype. Silica NPs rescaled the longevity effect of genetic interventions targeting the IGF-1/insulin-like signaling pathway. Comparative mass spectrometry revealed that increased insolubility of proteins with important functions in proteostasis is a shared phenotype of intrinsic- and pollution-induced aging supporting the hypothesis that proteostasis is a central resilience pathway controlling lifespan and aging. The presented data demonstrate that pollutants corrupt intrinsic aging pathways, which results in premature aging phenotypes. Reducing pollution is therefore an important step to increase healthy aging and prolong life expectancies on a population level in humans and animals.

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Section: Resultsmentioning

confidence: 99%

Pollutants corrupt resilience pathways of aging in the nematode C. elegans

Scharf

Limke

Guehrs

et al. 2021

Preprint

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show abstract

“…In addition to proteolytic activity, chaperone-like functions of Lon have also been reported in eukaryotic cells. The human Lon protease LONP1 is a mitochondrial matrix protein that, in conjunction with mitochondrial HSP70, promotes protein folding [ 25 ]. Lon plays a vital role in enhancing cell survival by maintaining the stability of the Hsp60–mtHsp70 complex [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Essential roles of Lon protease in the morpho-physiological traits of the rice pathogen Burkholderia glumae

Goo

Hwang

2021

PLoS ONE

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The highly conserved ATP-dependent Lon protease plays important roles in diverse biological processes. The lon gene is usually nonessential for viability; however, lon mutants of several bacterial species, although viable, exhibit cellular defects. Here, we show that a lack of Lon protease causes pleiotropic effects in the rice pathogen Burkholderia glumae. The null mutation of lon produced three colony types, big (BLONB), normal (BLONN), and small (BLONS), in Luria–Bertani (LB) medium. Colonies of the BLONB and BLONN types were re-segregated upon subculture, while those of the BLONS type were too small to manipulate. The BLONN type was chosen for further studies, as only this type was fully genetically complemented. BLONN-type cells did not reach the maximum growth capacity, and their population decreased drastically after the stationary phase in LB medium. BLONN-type cells were defective in the biosynthesis of quorum sensing (QS) signals and exhibited reduced oxalate biosynthetic activity, causing environmental alkaline toxicity and population collapse. Addition of excessive N-octanoyl-homoserine lactone (C8-HSL) to BLONN-type cell cultures did not fully restore oxalate biosynthesis, suggesting that the decrease in oxalate biosynthesis in BLONN-type cells was not due to insufficient C8-HSL. Co-expression of lon and tofR in Escherichia coli suggested that Lon negatively affects the TofR level in a C8-HSL-dependent manner. Lon protease interacted with the oxalate biosynthetic enzymes, ObcA and ObcB, indicating potential roles for the oxalate biosynthetic activity. These results suggest that Lon protease influences colony morphology, growth, QS system, and oxalate biosynthesis in B. glumae.

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“…CLPXP is a complex constituted by two components, the serine protease ClpP and the chaperone ClpX, that recognizes and delivers the protein substrates to ClpP for degradation ( 94 ). Mitochondrial LON protease plays a central role in the PQC in the mitochondrial matrix by removing unfolded and oxidized proteins and promoting the folding of imported proteins through interaction with the chaperone mtHSP70 ( 95 , 96 ).…”

Section: Mitochondrial Protein Quality Controlmentioning

confidence: 99%

Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy

et al. 2021

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Extensive metabolic remodeling is a fundamental feature of cancer cells. Although early reports attributed such remodeling to a loss of mitochondrial functions, it is now clear that mitochondria play central roles in cancer development and progression, from energy production to synthesis of macromolecules, from redox modulation to regulation of cell death. Biosynthetic pathways are also heavily affected by the metabolic rewiring, with protein synthesis dysregulation at the hearth of cellular transformation. Accumulating evidence in multiple organisms shows that the metabolic functions of mitochondria are tightly connected to protein synthesis, being assembly and activity of respiratory complexes highly dependent on de novo synthesis of their components. In turn, protein synthesis within the organelle is tightly connected with the cytosolic process. This implies an entire network of interactions and fine-tuned regulations that build up a completely under-estimated level of complexity. We are now only preliminarily beginning to reconstitute such regulatory level in human cells, and to perceive its role in diseases. Indeed, disruption or alterations of these connections trigger conditions of proteotoxic and energetic stress that could be potentially exploited for therapeutic purposes. In this review, we summarize the available literature on the coordinated regulation of mitochondrial and cytosolic mRNA translation, and their effects on the integrity of the mitochondrial proteome and functions. Finally, we highlight the potential held by this topic for future research directions and for the development of innovative therapeutic approaches.

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LONP1 and mtHSP70 cooperate to promote mitochondrial protein folding

Cited by 73 publications

References 37 publications

Pollutants corrupt resilience pathways of aging in the nematode C. elegans

Pollutants corrupt resilience pathways of aging in the nematode C. elegans

Essential roles of Lon protease in the morpho-physiological traits of the rice pathogen Burkholderia glumae

Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy

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