Intra-mitochondrial proteostasis is directly coupled to alpha-synuclein and Amyloid β 1-42 pathology

AbstractMitochondria have long been implicated in Parkinson’s disease (PD), however, it is not clear how mitochondrial impairment and alpha-synuclein pathology are coupled. We report here that intra-mitochondrial protein homeostasis plays a major role in alpha-synuclein fibril elongation, as interference with intra-mitochondrial proteases and mitochondrial protein import significantly aggravate alpha-synuclein aggregation. In contrast, direct inhibition of mitochondrial complex I, increase in intracellular calcium concentration or formation of reactive oxygen species (ROS), all of which have been associated with mitochondrial stress, did not affect alpha-synuclein pathology. We further demonstrate that similar mechanisms are involved in Amyloid β 1-42 (Aβ42) aggregation, suggesting that mitochondria are directly capable of influencing cytosolic protein homeostasis of aggregation-prone proteins.

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Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating other proteins aggregation

10.1101/2021.05.02.442342 ◽

2021 ◽

Author(s):

Urszula Nowicka ◽

Piotr Chroscicki ◽

Karen Stroobants ◽

Maria Sladowska ◽

Michal Turek ◽

...

Keyword(s):

Protein Import ◽

Mitochondrial Protein ◽

Amyloid Β ◽

Mitochondrial Proteins ◽

Protein Homeostasis ◽

Mitochondrial Protein Import ◽

Protein Levels ◽

Proteotoxic Stress ◽

Encoded Proteins ◽

Related Proteins

Mitochondria are organelles with their own genomes but rely on the import of nuclear-encoded proteins synthesized by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins may cause proteotoxic stress, and to identify which response mechanisms may be in place to respond to it. Here, we report that upon mitochondrial protein import impairment, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. In turn, these deposits cause further cytosolic accumulation of other mitochondrial and disease-related proteins, including α-synuclein and amyloid β. This aberrant accumulation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses, both at the transcriptomic and protein levels. Our results provide evidence that mitochondrial dysfunction, and specifically protein import defects, can contribute to protein homeostasis impairment, thus revealing a possible molecular mechanism for mitochondrial involvement in neurodegenerative diseases.

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Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins

eLife ◽

10.7554/elife.65484 ◽

2021 ◽

Vol 10 ◽

Author(s):

Urszula Nowicka ◽

Piotr Chroscicki ◽

Karen Stroobants ◽

Maria Sladowska ◽

Michal Turek ◽

...

Keyword(s):

Protein Import ◽

Mitochondrial Protein ◽

Amyloid Β ◽

Mitochondrial Proteins ◽

Protein Homeostasis ◽

Mitochondrial Protein Import ◽

Protein Levels ◽

Proteotoxic Stress ◽

Encoded Proteins ◽

Related Proteins

Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases.

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

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011650 ◽

2020 ◽

Vol 295 (30) ◽

pp. 10138-10152 ◽

Cited By ~ 3

Author(s):

Janin Lautenschläger ◽

Sara Wagner-Valladolid ◽

Amberley D. Stephens ◽

Ana Fernández-Villegas ◽

Colin Hockings ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Protein Import ◽

Protein Quality ◽

Neurodegenerative Disorder ◽

Mitochondrial Protein ◽

Amyloid Β ◽

Ubiquitin Proteasome System ◽

Protein Homeostasis ◽

Mitochondrial Inhibitors ◽

Ubiquitin Proteasome

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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Mitochondrial protein import regulates cytosolic protein homeostasis and neuronal integrity

Autophagy ◽

10.1080/15548627.2018.1474991 ◽

2018 ◽

Vol 14 (8) ◽

pp. 1293-1309 ◽

Cited By ~ 17

Author(s):

Wei Liu ◽

Xiuying Duan ◽

Xuefei Fang ◽

Weina Shang ◽

Chao Tong

Keyword(s):

Protein Import ◽

Mitochondrial Protein ◽

Protein Homeostasis ◽

Mitochondrial Protein Import ◽

Cytosolic Protein

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Cytosolic Quality Control of Mitochondrial Protein Precursors—The Early Stages of the Organelle Biogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms23010007 ◽

2021 ◽

Vol 23 (1) ◽

pp. 7

Author(s):

Anna M. Lenkiewicz ◽

Magda Krakowczyk ◽

Piotr Bragoszewski

Keyword(s):

Quality Control ◽

Protein Import ◽

Mitochondrial Protein ◽

Ubiquitin Proteasome System ◽

Vital Role ◽

Protein Homeostasis ◽

Organelle Biogenesis ◽

Mitochondrial Protein Import ◽

Ubiquitin Proteasome ◽

Cellular Pathways

With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.

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