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Trends in Pharmacological Sciences Aug 2023Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma.... (Review)
Review
Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma. However, PIs are not curative, and overcoming PI resistance to extend patient survival remains a major unmet need. Recent strategies to overcome PI resistance, including inhibiting alternative protein homeostasis pathways and targeting the mitochondrion as a nexus of metabolic adaptation to PIs, are gaining momentum. However, these focused approaches may be surpassed or even obviated by quickly emerging immunotherapy strategies that do not selectively target PI resistance mechanisms but are highly efficacious in PI-resistant disease, nonetheless. Informed by insights from these promising areas of research moving in parallel, we propose that pharmacological strategies to enforce immunotherapeutic vulnerabilities in resistant disease may provide a unified outlook to overcome PI resistance in a 'new era' of myeloma treatment.
Topics: Humans; Proteasome Inhibitors; Multiple Myeloma; Mitochondria; Immunotherapy; Drug Resistance, Neoplasm
PubMed: 37344251
DOI: 10.1016/j.tips.2023.05.006 -
Mitochondrion Nov 2023Allotopic expression is the functional transfer of an organellar gene to the nucleus, followed by synthesis of the gene product in the cytosol and import into the... (Review)
Review
Allotopic expression is the functional transfer of an organellar gene to the nucleus, followed by synthesis of the gene product in the cytosol and import into the appropriate organellar sub compartment. Here, we focus on mitochondrial genes encoding OXPHOS subunits that were naturally transferred to the nucleus, and critically review experimental evidence that claim their allotopic expression. We emphasize aspects that may have been overlooked before, i.e., when modifying a mitochondrial gene for allotopic expression━besides adapting the codon usage and including sequences encoding mitochondrial targeting signals━three additional constraints should be considered: (i) the average apparent free energy of membrane insertion (μΔG) of the transmembrane stretches (TMS) in proteins earmarked for the inner mitochondrial membrane, (ii) the final, functional topology attained by each membrane-bound OXPHOS subunit; and (iii) the defined mechanism by which the protein translocator TIM23 sorts cytosol-synthesized precursors. The mechanistic constraints imposed by TIM23 dictate the operation of two pathways through which alpha-helices in TMS are sorted, that eventually determine the final topology of membrane proteins. We used the biological hydrophobicity scale to assign an average apparent free energy of membrane insertion (μΔG) and a "traffic light" color code to all TMS of OXPHOS membrane proteins, thereby predicting which are more likely to be internalized into mitochondria if allotopically produced. We propose that the design of proteins for allotopic expression must make allowance for μΔG maximization of highly hydrophobic TMS in polypeptides whose corresponding genes have not been transferred to the nucleus in some organisms.
Topics: Mitochondria; Mitochondrial Membranes; Membrane Proteins; Genes, Mitochondrial; Protein Transport; Saccharomyces cerevisiae Proteins
PubMed: 37739243
DOI: 10.1016/j.mito.2023.09.004 -
Advanced Drug Delivery Reviews Sep 2023Limited by spatial and temporal resolution, traditional optical microscopy cannot image the delicate ultra-structure organelles and sub-organelles. The emergence of... (Review)
Review
Limited by spatial and temporal resolution, traditional optical microscopy cannot image the delicate ultra-structure organelles and sub-organelles. The emergence of super-resolution microscopy makes it possible. In this review, we focus on mitochondria. We summarize the process of mitochondrial dynamics, the primary proteins that regulate mitochondrial morphology, the diseases related to mitochondrial dynamics. The purpose is to apply super-resolution microscopy developed during recent years to the mitochondrial research. By providing the right research tools, we will help to promote the application of this technique to the in-depth elucidation of the pathogenesis of diseases related to mitochondrial dynamics, assistdiagnosis and develop the therapeutic treatment.
Topics: Humans; Microscopy; Mitochondria; Organelles
PubMed: 37536507
DOI: 10.1016/j.addr.2023.115043 -
Experimental & Molecular Medicine Dec 2023Mitochondria participate in a wide range of cellular processes. One essential function of mitochondria is to be a platform for antiviral signaling proteins during the... (Review)
Review
Mitochondria participate in a wide range of cellular processes. One essential function of mitochondria is to be a platform for antiviral signaling proteins during the innate immune response to viral infection. Recently, studies have revealed that mitochondrion-derived DNAs and RNAs are recognized as non-self molecules and act as immunogenic ligands. More importantly, the cytosolic release of these mitochondrial nucleic acids (mt-NAs) is closely associated with the pathogenesis of human diseases accompanying aberrant immune activation. The release of mitochondrial DNAs (mtDNAs) via BAX/BAK activation and/or VDAC1 oligomerization activates the innate immune response and inflammasome assembly. In addition, mitochondrial double-stranded RNAs (mt-dsRNAs) are sensed by pattern recognition receptors in the cytosol to induce type I interferon expression and initiate apoptotic programs. Notably, these cytosolic mt-NAs also mediate adipocyte differentiation and contribute to mitogenesis and mitochondrial thermogenesis. In this review, we summarize recent studies of innate immune signaling pathways regulated by mt-NAs, human diseases associated with mt-NAs, and the emerging physiological roles of mt-NAs.
Topics: Humans; Nucleic Acids; Immunity, Innate; Signal Transduction; Receptors, Pattern Recognition; Mitochondria
PubMed: 38036728
DOI: 10.1038/s12276-023-01121-x -
Journal of Translational Medicine Oct 2023Copper (Cu) is an essential element that is involved in a variety of biochemical processes. Both deficiency and accumulation of Cu are associated with various diseases;... (Review)
Review
Copper (Cu) is an essential element that is involved in a variety of biochemical processes. Both deficiency and accumulation of Cu are associated with various diseases; and a high amount of accumulated Cu in cells can be fatal. The production of reactive oxygen species (ROS), oxidative stress, and cuproptosis are among the proposed mechanisms of copper toxicity at high concentrations. Elesclomol (ELC) is a mitochondrion-targeting agent discovered for the treatment of solid tumors. In this review, we summarize the synthesis of this drug, its mechanisms of action, and the current status of its applications in the treatment of various diseases such as cancer, tuberculosis, SARS-CoV-2 infection, and other copper-associated disorders. We also provide some detailed information about future directions to improve its clinical performance.
Topics: Humans; Copper; Antineoplastic Agents; Oxidative Stress; Neoplasms; Mitochondria
PubMed: 37864163
DOI: 10.1186/s12967-023-04533-5 -
Journal of Molecular Medicine (Berlin,... Dec 2023The unfolded protein response (UPR) is a cellular stress response mechanism induced by the accumulation of unfolded or misfolded proteins. Within the endoplasmic... (Review)
Review
The unfolded protein response (UPR) is a cellular stress response mechanism induced by the accumulation of unfolded or misfolded proteins. Within the endoplasmic reticulum and mitochondria, a dynamic balance exists between protein folding mechanisms and unfolded protein levels under normal conditions. Disruption of this balance or an accumulation of unfolded proteins in these organelles can result in stress responses and UPR. The UPR restores organelle homeostasis and promotes cell survival by increasing the expression of chaperone proteins, regulating protein quality control systems, and enhancing the protein degradation pathway. However, prolonged or abnormal UPR can also have negative effects, including cell death. Therefore, many diseases, especially neurodegenerative diseases, are associated with UPR dysfunction. Neurodegenerative diseases are characterized by misfolded proteins accumulating and aggregating, and neuronal cells are particularly sensitive to misfolded proteins and are prone to degeneration. Many studies have shown that the UPR plays an important role in the pathogenesis of neurodegenerative diseases. Here, we will discuss the possible contributions of the endoplasmic reticulum unfolded protein response (UPR) and the mitochondrial unfolded protein response (UPR) in the development of several neurodegenerative diseases.
Topics: Humans; Neurodegenerative Diseases; Endoplasmic Reticulum Stress; Unfolded Protein Response; Endoplasmic Reticulum; Mitochondria
PubMed: 37817014
DOI: 10.1007/s00109-023-02382-9 -
Advanced Drug Delivery Reviews Sep 2023Significant evidences indicate that sub-cellular organelle dynamics is critical for both physiological and pathological events and therefore may be attractive drug... (Review)
Review
Significant evidences indicate that sub-cellular organelle dynamics is critical for both physiological and pathological events and therefore may be attractive drug targets displaying great therapeutic potential. Although the basic biological mechanism underlying the dynamics of intracellular organelles has been extensively studied, relative drug development is still limited. In the present review, we show that due to the development of technical advanced imaging tools, especially live cell imaging methods, intracellular organelle dynamics (including mitochondrial dynamics and membrane contact sites) can be dissected at the molecular level. Based on these identified molecular targets, we review and discuss the potential of drug development to target organelle dynamics, especially mitochondria dynamics and ER-organelle membrane contact dynamics, in the central nervous system for treating human diseases, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.
Topics: Humans; Mitochondria; Neurodegenerative Diseases; Parkinson Disease; Central Nervous System; Drug Development; Central Nervous System Agents
PubMed: 37516410
DOI: 10.1016/j.addr.2023.115025 -
Eye (London, England) Aug 2023Historically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue,... (Review)
Review
Historically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue, mitochondrial diseases frequently involve the eye, resulting in a range of ophthalmic manifestations including progressive external ophthalmoplegia, retinopathy and optic neuropathy, as well as deficiencies of the retrochiasmal visual pathway. With the wider availability of genetic testing in clinical practice, it is now recognised that genotype-phenotype correlations in mitochondrial diseases can be imprecise: many classic syndromes can be associated with multiple genes and genetic variants, and the same genetic variant can have multiple clinical presentations, including subclinical ophthalmic manifestations in individuals who are otherwise asymptomatic. Previously considered rare diseases with no effective treatments, considerable progress has been made in our understanding of mitochondrial diseases with new therapies emerging, in particular, gene therapy for inherited optic neuropathies.
Topics: Humans; Syndrome; Mitochondrial Diseases; Mitochondria; Optic Nerve Diseases; Retinal Diseases
PubMed: 37185957
DOI: 10.1038/s41433-023-02523-x -
Methods in Molecular Biology (Clifton,... 2024Plastids are semi-autonomous organelles like mitochondria and derive from a cyanobacterial ancestor that was engulfed by a host cell. During evolution, they have... (Review)
Review
Plastids are semi-autonomous organelles like mitochondria and derive from a cyanobacterial ancestor that was engulfed by a host cell. During evolution, they have recruited proteins originating from the nuclear genome, and only parts of their ancestral metabolic properties were conserved and optimized to limit functional redundancy with other cell compartments. Furthermore, large disparities in metabolic functions exist among various types of plastids, and the characterization of their various metabolic properties is far from being accomplished. In this review, we provide an overview of the main functions, known to be achieved by plastids or shared by plastids and other compartments of the cell. In short, plastids appear at the heart of all main plant functions.
Topics: Plastids; Mitochondria
PubMed: 38502499
DOI: 10.1007/978-1-0716-3726-5_5 -
Human Molecular Genetics May 2024Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical... (Review)
Review
Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical barrier to separate transcription and translation, nor is there evidence that quality control surveillance pathways are active to prevent translation on faulty mRNA transcripts. Mitochondrial ribosomes synthesize 13 hydrophobic proteins that require co-translational insertion into the inner membrane of the organelle. To maintain the integrity of the inner membrane, which is essential for organelle function, requires responsive quality control mechanisms to recognize aberrations in protein synthesis. In this review, we explore how defects in mitochondrial protein synthesis can arise due to the culmination of inherent mistakes that occur throughout the steps of gene expression. In turn, we examine the stepwise series of quality control processes that are needed to eliminate any mistakes that would perturb organelle homeostasis. We aim to provide an integrated view on the quality control mechanisms of mitochondrial protein synthesis and to identify promising avenues for future research.
Topics: Humans; Protein Biosynthesis; Mitochondrial Proteins; Mitochondria; DNA, Mitochondrial; RNA, Messenger; Mitochondrial Ribosomes; Animals
PubMed: 38280230
DOI: 10.1093/hmg/ddae012