-
International Journal of Molecular... Mar 2022Human mitochondrial disorders impact tissues with high energetic demands and can be associated with cardiac muscle disease (cardiomyopathy) and early mortality. However,... (Review)
Review
Human mitochondrial disorders impact tissues with high energetic demands and can be associated with cardiac muscle disease (cardiomyopathy) and early mortality. However, the mechanistic link between mitochondrial disease and the development of cardiomyopathy is frequently unclear. In addition, there is often marked phenotypic heterogeneity between patients, even between those with the same genetic variant, which is also not well understood. Several of the mitochondrial cardiomyopathies are related to defects in the maintenance of mitochondrial protein homeostasis, or proteostasis. This essential process involves the importing, sorting, folding and degradation of preproteins into fully functional mature structures inside mitochondria. Disrupted mitochondrial proteostasis interferes with mitochondrial energetics and ATP production, which can directly impact cardiac function. An inability to maintain proteostasis can result in mitochondrial dysfunction and subsequent mitophagy or even apoptosis. We review the known mitochondrial diseases that have been associated with cardiomyopathy and which arise from mutations in genes that are important for mitochondrial proteostasis. Genes discussed include DnaJ heat shock protein family member C19 (), mitochondrial import inner membrane translocase subunit TIM16 (), translocase of the inner mitochondrial membrane 50 (), mitochondrial intermediate peptidase (), X-prolyl-aminopeptidase 3 (), HtraA serine peptidase 2 (), caseinolytic mitochondrial peptidase chaperone subunit B () and heat shock 60-kD protein 1 (HSPD1). The identification and description of disorders with a shared mechanism of disease may provide further insights into the disease process and assist with the identification of potential therapeutics.
Topics: Cardiomyopathies; HSP40 Heat-Shock Proteins; Homeostasis; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins; Peptide Hydrolases; Protein Transport; Proteostasis
PubMed: 35328774
DOI: 10.3390/ijms23063353 -
Journal of Cell Science Aug 2023Peroxisomes are involved in a multitude of metabolic and catabolic pathways, as well as the innate immune system. Their dysfunction is linked to severe... (Review)
Review
Peroxisomes are involved in a multitude of metabolic and catabolic pathways, as well as the innate immune system. Their dysfunction is linked to severe peroxisome-specific diseases, as well as cancer and neurodegenerative diseases. To ensure the ability of peroxisomes to fulfill their many roles in the organism, more than 100 different proteins are post-translationally imported into the peroxisomal membrane and matrix, and their functionality must be closely monitored. In this Review, we briefly discuss the import of peroxisomal membrane proteins, and we emphasize an updated view of both classical and alternative peroxisomal matrix protein import pathways. We highlight different quality control pathways that ensure the degradation of dysfunctional peroxisomal proteins. Finally, we compare peroxisomal matrix protein import with other systems that transport folded proteins across membranes, in particular the twin-arginine translocation (Tat) system and the nuclear pore.
Topics: Membrane Proteins; Peroxisomes; Protein Transport; Intracellular Membranes
PubMed: 37552037
DOI: 10.1242/jcs.260999 -
Biomolecules Jul 2020Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize... (Review)
Review
Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors utilize a specialized translocation pathway dedicated to the biogenesis of carriers and related proteins, the carrier translocase of the inner membrane (TIM22) pathway. After recognition and import through the mitochondrial outer membrane via the translocase of the outer membrane (TOM) complex, carrier precursors are ushered through the intermembrane space by hexameric TIM chaperones and ultimately integrated into the inner membrane by the TIM22 carrier translocase. Recent advances have shed light on the mechanisms of TOM translocase and TIM chaperone function, uncovered an unexpected versatility of the machineries, and revealed novel components and functional crosstalk of the human TIM22 translocase.
Topics: Biological Transport; Carrier Proteins; Humans; Membrane Transport Proteins; Mitochondria; Mitochondrial Membranes; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Signal Transduction
PubMed: 32645990
DOI: 10.3390/biom10071008 -
Cell Death & Disease Nov 2023Though TDP-43 protein can be translocated into mitochondria and causes mitochondrial damage in TDP-43 proteinopathy, little is known about how TDP-43 is imported into...
Though TDP-43 protein can be translocated into mitochondria and causes mitochondrial damage in TDP-43 proteinopathy, little is known about how TDP-43 is imported into mitochondria. In addition, whether mitochondrial damage is caused by mitochondrial mislocalization of TDP-43 or a side effect of mitochondria-mediated TDP-43 degradation remains to be investigated. Here, our bioinformatical analyses reveal that mitophagy receptor gene FUNDC1 is co-expressed with TDP-43, and both TDP-43 and FUNDC1 expression is correlated with genes associated with mitochondrial protein import pathway in brain samples of patients diagnosed with TDP-43 proteinopathy. FUNDC1 promotes mitochondrial translocation of TDP-43 possibly by promoting TDP-43-TOM70 and DNAJA2-TOM70 interactions, which is independent of the LC3 interacting region of FUNDC1 in cellular experiments. In the transgenic fly model of TDP-43 proteinopathy, overexpressing FUNDC1 enhances TDP-43 induced mitochondrial damage, whereas down-regulating FUNDC1 reverses TDP-43 induced mitochondrial damage. FUNDC1 regulates mitochondria-mediated TDP-43 degradation not only by regulating mitochondrial TDP-43 import, but also by increasing LONP1 level and by activating mitophagy, which plays important roles in cytosolic TDP-43 clearance. Together, this study not only uncovers the mechanism of mitochondrial TDP-43 import, but also unravels the active role played by mitochondria in regulating TDP-43 homeostasis.
Topics: Humans; ATP-Dependent Proteases; DNA-Binding Proteins; HSP40 Heat-Shock Proteins; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Mitophagy; TDP-43 Proteinopathies
PubMed: 37951930
DOI: 10.1038/s41419-023-06261-6 -
Biochemical Society Transactions Feb 2020Chloroplasts are photosynthetic plant organelles descended from a bacterial ancestor. The vast majority of chloroplast proteins are synthesized in the cytosol and then... (Review)
Review
Chloroplasts are photosynthetic plant organelles descended from a bacterial ancestor. The vast majority of chloroplast proteins are synthesized in the cytosol and then imported into the chloroplast post-translationally. Translocation complexes exist in the organelle's outer and inner envelope membranes (termed TOC and TIC, respectively) to facilitate protein import. These systems recognize chloroplast precursor proteins and mediate their import in an energy-dependent manner. However, many unanswered questions remain regarding mechanistic details of the import process and the participation and functions of individual components; for example, the cytosolic events that mediate protein delivery to chloroplasts, the composition of the TIC apparatus, and the nature of the protein import motor all require resolution. The flux of proteins through TOC and TIC varies greatly throughout development and in response to specific environmental cues. The import process is, therefore, tightly regulated, and it has emerged that the ubiquitin-proteasome system (UPS) plays a key role in this regard, acting at several different steps in the process. The UPS is involved in: the selective degradation of transcription factors that co-ordinate the expression of chloroplast precursor proteins; the removal of unimported chloroplast precursor proteins in the cytosol; the inhibition of chloroplast biogenesis pre-germination; and the reconfiguration of the TOC apparatus in response to developmental and environmental signals in a process termed chloroplast-associated protein degradation. In this review, we highlight recent advances in our understanding of protein import into chloroplasts and how this process is regulated by the UPS.
Topics: Chloroplast Proteins; Chloroplasts; Cytosol; Organelles; Photosynthesis; Plant Proteins; Plants; Proteasome Endopeptidase Complex; Protein Precursors; Protein Transport; Proteolysis; Ubiquitin
PubMed: 31922184
DOI: 10.1042/BST20190274 -
Seminars in Cell & Developmental Biology Jul 2023The biogenesis of mitochondria requires the coordinated expression of the nuclear and the mitochondrial genomes. However, the vast majority of gene products within the... (Review)
Review
The biogenesis of mitochondria requires the coordinated expression of the nuclear and the mitochondrial genomes. However, the vast majority of gene products within the organelle are encoded in the nucleus, synthesized in the cytosol, and imported into mitochondria via the protein import machinery, which permit the entry of proteins to expand the mitochondrial network. Once inside, proteins undergo a maturation and folding process brought about by enzymes comprising the unfolded protein response (UPR). Protein import and UPR activity must be synchronized and matched with mtDNA-encoded subunit synthesis for proper assembly of electron transport chain complexes to avoid proteotoxicity. This review discusses the functions of the import and UPR systems in mammalian skeletal muscle, as well as how exercise alters the equilibrium of these pathways in a time-dependent manner, leading to a new steady state of mitochondrial content resulting in enhanced oxidative capacity and improved muscle health.
Topics: Animals; Mitochondrial Proteins; Mitochondria; Muscle, Skeletal; Unfolded Protein Response; Adaptation, Physiological; Mammals
PubMed: 35063351
DOI: 10.1016/j.semcdb.2022.01.002 -
Current Opinion in Cell Biology Apr 2022More than 95% of mitochondrial proteins are encoded in the nucleus, synthesised in the cytosol and imported into the organelle. The evolution of mitochondrial protein... (Review)
Review
More than 95% of mitochondrial proteins are encoded in the nucleus, synthesised in the cytosol and imported into the organelle. The evolution of mitochondrial protein import systems was therefore a prerequisite for the conversion of the α-proteobacterial mitochondrial ancestor into an organelle. Here, I review that the origin of the mitochondrial outer membrane import receptors can best be understood by convergent evolution. Subsequently, I discuss an evolutionary scenario that was proposed to explain the diversification of the inner membrane carrier protein translocases between yeast and mammals. Finally, I illustrate a scenario that can explain how the two specialised inner membrane protein translocase complexes found in most eukaryotes were reduced to a single multifunctional one in trypanosomes.
Topics: Animals; Carrier Proteins; Mammals; Membrane Proteins; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Protein Transport; Saccharomyces cerevisiae
PubMed: 35390639
DOI: 10.1016/j.ceb.2022.102077 -
FEBS Letters Apr 2021The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction... (Review)
Review
The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co-ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.
Topics: Animals; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Neoplasm Proteins; Neoplasms; Neurodegenerative Diseases; Protein Transport
PubMed: 33314127
DOI: 10.1002/1873-3468.14022 -
Journal of Experimental Botany Dec 2014The majority of more than 1000 proteins present in mitochondria are imported from nuclear-encoded, cytosolically synthesized precursor proteins. This impressive feat of... (Review)
Review
The majority of more than 1000 proteins present in mitochondria are imported from nuclear-encoded, cytosolically synthesized precursor proteins. This impressive feat of transport and sorting is achieved by the combined action of targeting signals on mitochondrial proteins and the mitochondrial protein import apparatus. The mitochondrial protein import apparatus is composed of a number of multi-subunit protein complexes that recognize, translocate, and assemble mitochondrial proteins into functional complexes. While the core subunits involved in mitochondrial protein import are well conserved across wide phylogenetic gaps, the accessory subunits of these complexes differ in identity and/or function when plants are compared with Saccharomyces cerevisiae (yeast), the model system for mitochondrial protein import. These differences include distinct protein import receptors in plants, different mechanistic operation of the intermembrane protein import system, the location and activity of peptidases, the function of inner-membrane translocases in linking the outer and inner membrane, and the association/regulation of mitochondrial protein import complexes with components of the respiratory chain. Additionally, plant mitochondria share proteins with plastids, i.e. dual-targeted proteins. Also, the developmental and cell-specific nature of mitochondrial biogenesis is an aspect not observed in single-celled systems that is readily apparent in studies in plants. This means that plants provide a valuable model system to study the various regulatory processes associated with protein import and mitochondrial biogenesis.
Topics: Mitochondria; Plant Proteins; Plants; Protein Processing, Post-Translational; Protein Transport; Signal Transduction
PubMed: 25324401
DOI: 10.1093/jxb/eru399 -
Frontiers in Genetics 2023The spectacular diversity of plastids in non-green organs such as flowers, fruits, roots, tubers, and senescing leaves represents a Universe of metabolic processes in... (Review)
Review
The spectacular diversity of plastids in non-green organs such as flowers, fruits, roots, tubers, and senescing leaves represents a Universe of metabolic processes in higher plants that remain to be completely characterized. The endosymbiosis of the plastid and the subsequent export of the ancestral cyanobacterial genome to the nuclear genome, and adaptation of the plants to all types of environments has resulted in the emergence of diverse and a highly orchestrated metabolism across the plant kingdom that is entirely reliant on a complex protein import and translocation system. The TOC and TIC translocons, critical for importing nuclear-encoded proteins into the plastid stroma, remain poorly resolved, especially in the case of TIC. From the stroma, three core pathways (cpTat, cpSec, and cpSRP) may localize imported proteins to the thylakoid. Non-canonical routes only utilizing TOC also exist for the insertion of many inner and outer membrane proteins, or in the case of some modified proteins, a vesicular import route. Understanding this complex protein import system is further compounded by the highly heterogeneous nature of transit peptides, and the varying transit peptide specificity of plastids depending on species and the developmental and trophic stage of the plant organs. Computational tools provide an increasingly sophisticated means of predicting protein import into highly diverse non-green plastids across higher plants, which need to be validated using proteomics and metabolic approaches. The myriad plastid functions enable higher plants to interact and respond to all kinds of environments. Unraveling the diversity of non-green plastid functions across the higher plants has the potential to provide knowledge that will help in developing climate resilient crops.
PubMed: 37007964
DOI: 10.3389/fgene.2023.969931