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

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

10.1101/561134 ◽

2019 ◽

Author(s):

Janin Lautenschläger ◽

Sara Wagner-Valladolid ◽

Amberley D. Stephens ◽

Ana Fernández-Villegas ◽

Colin Hockings ◽

...

Keyword(s):

Calcium Concentration ◽

Protein Import ◽

Mitochondrial Protein ◽

Amyloid Β ◽

Alpha Synuclein ◽

Protein Homeostasis ◽

Oxygen Species ◽

Direct Inhibition ◽

Mitochondrial Protein Import ◽

Alpha Synuclein Aggregation

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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Plant mitochondrial protein import: mechanisms and control

Functional Plant Biology ◽

10.1071/pp99064 ◽

1999 ◽

Vol 26 (8) ◽

pp. 725 ◽

Cited By ~ 1

Author(s):

James Whelan

Keyword(s):

Protein Import ◽

Current Knowledge ◽

Mitochondrial Protein ◽

Mitochondrial Proteins ◽

Mitochondrial Protein Import ◽

Future Directions ◽

Receptor Structure ◽

Processing Peptidase ◽

Targeting Signals ◽

And Control

The characterisation of components of the plant mitochondrial import apparatus along with the availability of over one hundred nuclear-encoded mitochondrial proteins allows the study of plant mitochondrial protein import in homologous systems. From these studies it has emerged that although similarities in the import process exist with other organisms, significance differences exist, such as receptor structure, location of processing peptidase and targeting signals. These differences mean that previous studies carried out in heterologous systems must be re-evaluated. Further studies into protein import in plants need to be directed at understanding the mechanism of import and how this process may be controlled. In this review the latter points will be dealt with in terms of summarising our current knowledge and possible future directions.

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Mitochondrial protein import: An unexpected disulfide bond

The Journal of Cell Biology ◽

10.1083/jcb.201607117 ◽

2016 ◽

Vol 214 (4) ◽

pp. 363-365 ◽

Cited By ~ 4

Author(s):

Dejana Mokranjac

Keyword(s):

Disulfide Bond ◽

Protein Import ◽

Protein Translocation ◽

Mitochondrial Protein ◽

Channel Gating ◽

Mitochondrial Proteins ◽

Mitochondrial Protein Import ◽

Cell Biol ◽

Molecular Nature

Most mitochondrial proteins are imported through the TIM23 translocation channel, the structure and molecular nature of which are still unclear. In this issue, Ramesh et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201602074) show that the TIM23 subunit Tim17 contains a disulfide bond that is crucial for protein translocation and channel gating.

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The peptidases involved in plant mitochondrial protein import

Journal of Experimental Botany ◽

10.1093/jxb/erz365 ◽

2019 ◽

Vol 70 (21) ◽

pp. 6005-6018 ◽

Cited By ~ 8

Author(s):

Abi S Ghifari ◽

Shaobai Huang ◽

Monika W Murcha

Keyword(s):

Mitochondrial Biogenesis ◽

Protein Import ◽

Mitochondrial Protein ◽

Mitochondrial Protein Import ◽

Mitochondrial Proteome ◽

Encoded Proteins

Mitochondrial biogenesis requires correct targeting and import of nuclear-encoded proteins to ensure the mitochondrial proteome responds to meet the plant’s energetic demands. Protein-degrading machineries also play key roles in protein import and mitochondrial biogenesis.

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From cytosol to mitochondria: the beginning of a protein journey

Biological Chemistry ◽

10.1515/hsz-2020-0110 ◽

2020 ◽

Vol 401 (6-7) ◽

pp. 645-661 ◽

Cited By ~ 5

Author(s):

Maria Clara Avendaño-Monsalve ◽

José Carlos Ponce-Rojas ◽

Soledad Funes

Keyword(s):

Mitochondrial Biogenesis ◽

Stress Responses ◽

Protein Import ◽

Protein Targeting ◽

Mitochondrial Protein ◽

Past Research ◽

Membrane Receptors ◽

Mitochondrial Proteins ◽

Mitochondrial Protein Import ◽

The Past

AbstractMitochondrial protein import is one of the key processes during mitochondrial biogenesis that involves a series of events necessary for recognition and delivery of nucleus-encoded/cytosol-synthesized mitochondrial proteins into the organelle. The past research efforts have mainly unraveled how membrane translocases ensure the correct protein sorting within the different mitochondrial subcompartments. However, early steps of recognition and delivery remain relatively uncharacterized. In this review, we discuss our current understanding about the signals on mitochondrial proteins, as well as in the mRNAs encoding them, which with the help of cytosolic chaperones and membrane receptors support protein targeting to the organelle in order to avoid improper localization. In addition, we discuss recent findings that illustrate how mistargeting of mitochondrial proteins triggers stress responses, aiming to restore cellular homeostasis.

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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 diseases caused by dysfunctional mitochondrial protein import

Biochemical Society Transactions ◽

10.1042/bst20180239 ◽

2018 ◽

Vol 46 (5) ◽

pp. 1225-1238 ◽

Cited By ~ 8

Author(s):

Thomas Daniel Jackson ◽

Catherine Sarah Palmer ◽

Diana Stojanovski

Keyword(s):

Mitochondrial Disease ◽

Genetic Disease ◽

Molecular Basis ◽

Protein Import ◽

Mitochondrial Protein ◽

Mitochondrial Diseases ◽

Mitochondrial Proteins ◽

Eukaryotic Cells ◽

Mitochondrial Protein Import ◽

Mitochondrial Proteome

Mitochondria are essential organelles which perform complex and varied functions within eukaryotic cells. Maintenance of mitochondrial health and functionality is thus a key cellular priority and relies on the organelle's extensive proteome. The mitochondrial proteome is largely encoded by nuclear genes, and mitochondrial proteins must be sorted to the correct mitochondrial sub-compartment post-translationally. This essential process is carried out by multimeric and dynamic translocation and sorting machineries, which can be found in all four mitochondrial compartments. Interestingly, advances in the diagnosis of genetic disease have revealed that mutations in various components of the human import machinery can cause mitochondrial disease, a heterogenous and often severe collection of disorders associated with energy generation defects and a multisystem presentation often affecting the cardiovascular and nervous systems. Here, we review our current understanding of mitochondrial protein import systems in human cells and the molecular basis of mitochondrial diseases caused by defects in these pathways.

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Cooperation of translocase complexes in mitochondrial protein import

The Journal of Cell Biology ◽

10.1083/jcb.200708199 ◽

2007 ◽

Vol 179 (4) ◽

pp. 585-591 ◽

Cited By ~ 56

Author(s):

Stephan Kutik ◽

Bernard Guiard ◽

Helmut E. Meyer ◽

Nils Wiedemann ◽

Nikolaus Pfanner

Keyword(s):

Outer Membrane ◽

Protein Import ◽

Protein Complexes ◽

Mitochondrial Protein ◽

Mitochondrial Proteins ◽

Intermembrane Space ◽

Mitochondrial Protein Import ◽

Inner Membrane ◽

Precursor Proteins ◽

Preprotein Translocation

Most mitochondrial proteins are synthesized in the cytosol and imported into one of the four mitochondrial compartments: outer membrane, intermembrane space, inner membrane, and matrix. Each compartment contains protein complexes that interact with precursor proteins and promote their transport. These translocase complexes do not act as independent units but cooperate with each other and further membrane complexes in a dynamic manner. We propose that a regulated coupling of translocases is important for the coordination of preprotein translocation and efficient sorting to intramitochondrial compartments.

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