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3 results on '"Lon peptidase 1 mitochondrial"'

1. Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

Author

Ana Fernández-Villegas, Gabriele S. Kaminski Schierle, Marcus Fantham, Janin Lautenschläger, Amberley D. Stephens, Sara Wagner-Valladolid, James D. Manton, Eric J. Rees, Colin Hockings, Ajay Kumar Mishra, Clemens F. Kaminski, Meng Lu, Lautenschläger, Janin [0000-0001-7788-7074], Stephens, Amberley D [0000-0002-7303-6392], Manton, James D [0000-0001-9260-3156], Kaminski Schierle, Gabriele S [0000-0002-1843-2202], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Proteases, amyloid-β (Aβ,), Amyloid, HtrA2/Omi, Nerve Tissue Proteins, Mitochondrion, Protein aggregation, Biochemistry, protein aggregation, Rats, Sprague-Dawley, 03 medical and health sciences, α-synuclein, neurodegenerative disease, amyloid-β (AB), Cell Line, Tumor, medicine, Animals, Humans, Molecular Biology, protein homeostasis, Lon peptidase 1 mitochondrial, Amyloid beta-Peptides, 030102 biochemistry & molecular biology, Serine-Arginine Splicing Factors, Chemistry, Neurodegeneration, neurodegeneration, HtrA serine peptidase 2, Lon protease, Molecular Bases of Disease, Parkinson Disease, Cell Biology, High-Temperature Requirement A Serine Peptidase 2, medicine.disease, Peptide Fragments, 3. Good health, Cell biology, Mitochondria, Rats, α-synuclein (a-synuclein), Cytosol, 030104 developmental biology, Proteostasis, alpha-Synuclein, Female
Abstract

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin-proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

Published
2020

2. Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies.

Author

Lautenschläger J, Wagner-Valladolid S, Stephens AD, Fernández-Villegas A, Hockings C, Mishra A, Manton JD, Fantham MJ, Lu M, Rees EJ, Kaminski CF, and Kaminski Schierle GS

Subjects
Amyloid beta-Peptides genetics, Animals, Cell Line, Tumor, Female, High-Temperature Requirement A Serine Peptidase 2 genetics, High-Temperature Requirement A Serine Peptidase 2 metabolism, Humans, Mitochondria genetics, Mitochondria pathology, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Parkinson Disease genetics, Parkinson Disease pathology, Peptide Fragments genetics, Rats, Rats, Sprague-Dawley, Serine-Arginine Splicing Factors genetics, Serine-Arginine Splicing Factors metabolism, alpha-Synuclein genetics, Amyloid beta-Peptides metabolism, Mitochondria metabolism, Parkinson Disease metabolism, Peptide Fragments metabolism, Proteostasis, alpha-Synuclein metabolism
Abstract

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin-proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies., Competing Interests: Conflict of interest—The authors declare no conflict of interest., (© 2020 Lautenschläger et al.)

Published
2020
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3. Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

Author

Lautenschläger, Janin, Wagner-Valladolid, Sara, Stephens, Amberley D, Fernández-Villegas, Ana, Hockings, Colin, Mishra, Ajay, Manton, James D, Fantham, Marcus J, Lu, Meng, Rees, Eric J, Kaminski, Clemens F, and Kaminski Schierle, Gabriele S

Subjects
amyloid-β (Aβ,), HtrA2/Omi, Nerve Tissue Proteins, protein aggregation, Rats, Sprague-Dawley, neurodegenerative disease, α-synuclein, amyloid-β (AB), Cell Line, Tumor, Animals, Humans, Lon peptidase 1 mitochondrial, protein homeostasis, Amyloid beta-Peptides, Serine-Arginine Splicing Factors, neurodegeneration, HtrA serine peptidase 2, Lon protease, Parkinson Disease, High-Temperature Requirement A Serine Peptidase 2, Peptide Fragments, 3. Good health, Mitochondria, Rats, α-synuclein (a-synuclein), Proteostasis, alpha-Synuclein, Female
Abstract

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin-proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

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