-
International Journal of Molecular... Jan 2023Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and... (Review)
Review
Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the oxidative phosphorylation system (OXPHOS). The rest of the proteins (99%) that function in mitochondria in the various pathways described above are nuclear-transcribed and synthesized as precursors in the cytosol. These proteins are imported into the mitochondria by the unique mitochondrial protein import system that consists of seven machineries. Proper functioning of the mitochondrial protein import system is crucial for optimal mitochondrial deliverables, as well as mitochondrial and cellular homeostasis. Impaired mitochondrial protein import leads to proteotoxic stress in both mitochondria and cytosol, inducing mitochondrial unfolded protein response (UPR). Altered UPR is associated with the development of various disease conditions including neurodegenerative and cardiovascular diseases, as well as cancer. This review sheds light on the molecular mechanisms underlying the import of nuclear-encoded mitochondrial proteins, the consequences of defective mitochondrial protein import, and the pathological conditions that arise due to altered UPR.
Topics: Mitochondrial Proteins; Mitochondria; Protein Transport; Cell Nucleus; Cytosol; Unfolded Protein Response
PubMed: 36768800
DOI: 10.3390/ijms24032479 -
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 -
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 -
The Biochemical Journal Aug 2021Mitochondria import about 1000 proteins that are produced as precursors on cytosolic ribosomes. Defects in mitochondrial protein import result in the accumulation of... (Review)
Review
Mitochondria import about 1000 proteins that are produced as precursors on cytosolic ribosomes. Defects in mitochondrial protein import result in the accumulation of non-imported precursor proteins and proteotoxic stress. The cell is equipped with different quality control mechanisms to monitor protein transport into mitochondria. First, molecular chaperones guide unfolded proteins to mitochondria and deliver non-imported proteins to proteasomal degradation. Second, quality control factors remove translocation stalled precursor proteins from protein translocases. Third, protein translocases monitor protein sorting to mitochondrial subcompartments. Fourth, AAA proteases of the mitochondrial subcompartments remove mislocalized or unassembled proteins. Finally, impaired efficiency of protein transport is an important sensor for mitochondrial dysfunction and causes the induction of cellular stress responses, which could eventually result in the removal of the defective mitochondria by mitophagy. In this review, we summarize our current understanding of quality control mechanisms that govern mitochondrial protein transport.
Topics: Animals; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Mitophagy; Models, Biological; Protein Precursors; Protein Transport; Quality Control
PubMed: 34436539
DOI: 10.1042/BCJ20190584 -
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 -
FEBS Letters Jun 2023Mitochondria contain 902 (yeast) to 1.136 (mouse, humans) verified proteins. Except for a very small number of mitochondrially encoded core components of the respiratory... (Review)
Review
Mitochondria contain 902 (yeast) to 1.136 (mouse, humans) verified proteins. Except for a very small number of mitochondrially encoded core components of the respiratory chain, mitochondrial proteins are encoded by nuclear genes and synthesized in the cytosol. Different import pathways direct proteins to their respective mitochondrial subcompartment (outer membrane, intermembrane space (IMS), inner membrane and matrix). Specific targeting signals in their sequence direct proteins to their target destination and allow the proteins to embark on their respective import pathway. The main import pathways are shown here on the poster and are introduced in the following, using the mitochondrial import system of the baker's yeast Saccharomyces cerevisiae as example. However, the mitochondrial import system of mammalian cells is highly similar and deviates only in minor aspects. Even the mitochondrial import machineries of less closely related eukaryotes, such as plants and trypanosomes, are very similar and adhere to the same general principles.
Topics: Humans; Animals; Mice; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondria; Mitochondrial Membranes; Protein Transport; Saccharomyces cerevisiae; Mitochondrial Proteins; Saccharomyces cerevisiae Proteins; Mammals
PubMed: 37021373
DOI: 10.1002/1873-3468.14614 -
Biological Chemistry May 2020Mitochondria import the vast majority of their proteins via dedicated protein machineries. The translocase of the outer membrane (TOM complex) forms the main entry site... (Review)
Review
Mitochondria import the vast majority of their proteins via dedicated protein machineries. The translocase of the outer membrane (TOM complex) forms the main entry site for precursor proteins that are produced on cytosolic ribosomes. Subsequently, different protein sorting machineries transfer the incoming preproteins to the mitochondrial outer and inner membranes, the intermembrane space, and the matrix. In this review, we highlight the recently discovered role of porin, also termed voltage-dependent anion channel (VDAC), in mitochondrial protein biogenesis. Porin forms the major channel for metabolites and ions in the outer membrane of mitochondria. Two different functions of porin in protein translocation have been reported. First, it controls the formation of the TOM complex by modulating the integration of the central receptor Tom22 into the mature translocase. Second, porin promotes the transport of carrier proteins toward the carrier translocase (TIM22 complex), which inserts these preproteins into the inner membrane. Therefore, porin acts as a coupling factor to spatially coordinate outer and inner membrane transport steps. Thus, porin links metabolite transport to protein import, which are both essential for mitochondrial function and biogenesis.
Topics: Humans; Mitochondria; Mitochondrial Proteins; Porins; Protein Transport; Saccharomyces cerevisiae
PubMed: 31967957
DOI: 10.1515/hsz-2019-0438 -
Brain, Behavior, and Immunity Feb 2024Neuroinflammation and microglial iron load are significant hallmarks found in several neurodegenerative diseases. In in vitro systems, microglia preferentially...
Neuroinflammation and microglial iron load are significant hallmarks found in several neurodegenerative diseases. In in vitro systems, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and it has been shown that iron can augment cellular inflammation, suggesting a feed-forward loop between mechanisms involved in iron import and inflammatory signaling. However, it is not understood how microglial iron import mechanisms contribute to inflammation in vivo, or whether altering a microglial iron-related gene affects the inflammatory response. These studies aimed to determine the effect of knocking down microglial iron import gene Slc11a2 on the inflammatory response in vivo. We generated a novel model of tamoxifen-inducible, microglial-specific Slc11a2 knockdown using Cx3cr1 mice. Transgenic male and female mice were administered intraperitoneal saline or lipopolysaccharide (LPS) and assessed for sickness behavior post-injection. Plasma cytokines and microglial bulk RNA sequencing (RNASeq) analyses were performed at 4 h post-LPS, and microglia were collected for gene expression analysis after 24 h. A subset of mice was assessed in a behavioral test battery following LPS-induced sickness recovery. Control male, but not female, mice significantly upregulated microglial Slc11a2 at 4 and 24 h following LPS. In Slc11a2 knockdown mice, we observed an improvement in the acute behavioral sickness response post-LPS in male, but not female, animals. Microglia from male, but not female, knockdown animals exhibited a significant decrease in LPS-provoked pro-inflammatory cytokine expression after 24 h. RNASeq data from male knockdown microglia 4 h post-LPS revealed a robust downregulation in inflammatory genes including Il6, Tnfα, and Il1β, and an increase in anti-inflammatory and homeostatic markers (e.g., Tgfbr1, Cx3cr1, and Trem2). This corresponded with a profound decrease in plasma pro-inflammatory cytokines 4 h post-LPS. At 4 h, male knockdown microglia also upregulated expression of markers of iron export, iron recycling, and iron homeostasis and decreased iron storage and import genes, along with pro-oxidant markers such as Cybb, Nos2, and Hif1α. Overall, this work elucidates how manipulating a specific gene involved in iron import in microglia alters acute inflammatory signaling and overall cell activation state in male mice. These data highlight a sex-specific link between a microglial iron import gene and the pro-inflammatory response to LPS in vivo, providing further insight into the mechanisms driving neuroinflammatory disease.
Topics: Animals; Female; Male; Mice; Cytokines; Inflammation; Iron; Lipopolysaccharides; Membrane Glycoproteins; Mice, Inbred C57BL; Microglia; Receptors, Immunologic
PubMed: 38141840
DOI: 10.1016/j.bbi.2023.12.020 -
Science Advances Feb 2024Lysosomal calcium (Ca) release is critical to cell signaling and is mediated by well-known lysosomal Ca channels. Yet, how lysosomes refill their Ca remains hitherto...
Lysosomal calcium (Ca) release is critical to cell signaling and is mediated by well-known lysosomal Ca channels. Yet, how lysosomes refill their Ca remains hitherto undescribed. Here, from an RNA interference screen in , we identify an evolutionarily conserved gene, , that facilitates lysosomal Ca entry in and mammalian cells. We found that its human homolog TMEM165, previously designated as a Ca/H exchanger, imports Ca pH dependently into lysosomes. Using two-ion mapping and electrophysiology, we show that TMEM165, hereafter referred to as human LCI, acts as a proton-activated, lysosomal Ca importer. Defects in lysosomal Ca channels cause several neurodegenerative diseases, and knowledge of lysosomal Ca importers may provide previously unidentified avenues to explore the physiology of Ca channels.
Topics: Animals; Humans; Calcium; Caenorhabditis elegans; Calcium Channels; Signal Transduction; Lysosomes; Calcium Signaling; Mammals; Antiporters; Cation Transport Proteins
PubMed: 38354239
DOI: 10.1126/sciadv.adk2317 -
Biological Chemistry Dec 2019Biogenesis and function of mitochondria depend on the import of about 1000 precursor proteins that are produced on cytosolic ribosomes. The translocase of the outer... (Review)
Review
Biogenesis and function of mitochondria depend on the import of about 1000 precursor proteins that are produced on cytosolic ribosomes. The translocase of the outer membrane (TOM) forms the entry gate for most proteins. After passage through the TOM channel, dedicated preprotein translocases sort the precursor proteins into the mitochondrial subcompartments. Many proteins have to be assembled into oligomeric membrane-integrated complexes in order to perform their functions. In this review, we discuss a dual role of mitochondrial preprotein translocases in protein translocation and oligomeric assembly, focusing on the biogenesis of the TOM complex and the respiratory chain. The sorting and assembly machinery (SAM) of the outer mitochondrial membrane forms a dynamic platform for coupling transport and assembly of TOM subunits. The biogenesis of the cytochrome c oxidase of the inner membrane involves a molecular circuit to adjust translation of mitochondrial-encoded core subunits to the availability of nuclear-encoded partner proteins. Thus, mitochondrial protein translocases not only import precursor proteins but can also support their assembly into functional complexes.
Topics: Carrier Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Protein Biosynthesis; Protein Transport; Ribosomes; Saccharomyces cerevisiae
PubMed: 31513529
DOI: 10.1515/hsz-2019-0310