Mitochondrial diseases caused by dysfunctional mitochondrial protein import

2018 ◽  
Vol 46 (5) ◽  
pp. 1225-1238 ◽  
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.

scholarly journals Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23

2019 ◽  
Vol 116 (33) ◽  
pp. 16593-16602 ◽  
Author(s):  
Svitlana Yablonska ◽  
Vinitha Ganesan ◽  
Lisa M. Ferrando ◽  
JinHo Kim ◽  
Anna Pyzel ◽  
...  
Keyword(s):  
Cell Lines ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Biological Significance ◽  
Intermembrane Space ◽  
Mutant Huntingtin ◽  
Mitochondrial Protein Import ◽  
Inner Membrane ◽  
Mitochondrial Proteome ◽  
Brain Tissues

Mutant huntingtin (mHTT), the causative protein in Huntington’s disease (HD), associates with the translocase of mitochondrial inner membrane 23 (TIM23) complex, resulting in inhibition of synaptic mitochondrial protein import first detected in presymptomatic HD mice. The early timing of this event suggests that it is a relevant and direct pathophysiologic consequence of mHTT expression. We show that, of the 4 TIM23 complex proteins, mHTT specifically binds to the TIM23 subunit and that full-length wild-type huntingtin (wtHTT) and mHTT reside in the mitochondrial intermembrane space. We investigated differences in mitochondrial proteome between wtHTT and mHTT cells and found numerous proteomic disparities between mHTT and wtHTT mitochondria. We validated these data by quantitative immunoblotting in striatal cell lines and human HD brain tissue. The level of soluble matrix mitochondrial proteins imported through the TIM23 complex is lower in mHTT-expressing cell lines and brain tissues of HD patients compared with controls. In mHTT-expressing cell lines, membrane-bound TIM23-imported proteins have lower intramitochondrial levels, whereas inner membrane multispan proteins that are imported via the TIM22 pathway and proteins integrated into the outer membrane generally remain unchanged. In summary, we show that, in mitochondria, huntingtin is located in the intermembrane space, that mHTT binds with high-affinity to TIM23, and that mitochondria from mHTT-expressing cells and brain tissues of HD patients have reduced levels of nuclearly encoded proteins imported through TIM23. These data demonstrate the mechanism and biological significance of mHTT-mediated inhibition of mitochondrial protein import, a mechanism likely broadly relevant to other neurodegenerative diseases.

Plant mitochondrial protein import: mechanisms and control

1999 ◽  
Vol 26 (8) ◽  
pp. 725 ◽  
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.

scholarly journals Mitochondrial protein import: An unexpected disulfide bond

2016 ◽  
Vol 214 (4) ◽  
pp. 363-365 ◽  
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.

scholarly journals The peptidases involved in plant mitochondrial protein import

2019 ◽  
Vol 70 (21) ◽  
pp. 6005-6018 ◽  
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.

scholarly journals From cytosol to mitochondria: the beginning of a protein journey

2020 ◽  
Vol 401 (6-7) ◽  
pp. 645-661 ◽  
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.

scholarly journals Events upstream of mitochondrial protein import limit the oxidative capacity of fibroblasts in multiple mitochondrial disease

2002 ◽  
Vol 1586 (2) ◽  
pp. 146-154 ◽  
Author(s):  
Arne A. Rungi ◽  
Andy Primeau ◽  
Lorraine Nunes Christie ◽  
Joseph W. Gordon ◽  
Brian H. Robinson ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Oxidative Capacity ◽  
Mitochondrial Protein Import

scholarly journals Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 432
Author(s):  
Hope I. Needs ◽  
Margherita Protasoni ◽  
Jeremy M. Henley ◽  
Julien Prudent ◽  
Ian Collinson ◽  
...  
Keyword(s):  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Functional Protein ◽  
Mitochondrial Protein Import ◽  
Complex Assembly ◽  
Respiratory Complex ◽  
And Function

The fact that >99% of mitochondrial proteins are encoded by the nuclear genome and synthesised in the cytosol renders the process of mitochondrial protein import fundamental for normal organelle physiology. In addition to this, the nuclear genome comprises most of the proteins required for respiratory complex assembly and function. This means that without fully functional protein import, mitochondrial respiration will be defective, and the major cellular ATP source depleted. When mitochondrial protein import is impaired, a number of stress response pathways are activated in order to overcome the dysfunction and restore mitochondrial and cellular proteostasis. However, prolonged impaired mitochondrial protein import and subsequent defective respiratory chain function contributes to a number of diseases including primary mitochondrial diseases and neurodegeneration. This review focuses on how the processes of mitochondrial protein translocation and respiratory complex assembly and function are interlinked, how they are regulated, and their importance in health and disease.

scholarly journals Mitochondrial Protein Import: Molecular Basis of the ATP-dependent Interaction of MtHsp70 with Tim44

2001 ◽  
Vol 277 (9) ◽  
pp. 6874-6880 ◽  
Author(s):  
Fernando Moro ◽  
Koji Okamoto ◽  
Mariel Donzeau ◽  
Walter Neupert ◽  
Michael Brunner
Keyword(s):  
Molecular Basis ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Mitochondrial Protein Import ◽  
Dependent Interaction

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

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.

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

eLife ◽  
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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