-
Biomolecules Jul 2023Mitochondria are often referred to as the "powerhouse" of the cell. However, this organelle has many more functions than simply satisfying the cells' metabolic needs.... (Review)
Review
Mitochondria are often referred to as the "powerhouse" of the cell. However, this organelle has many more functions than simply satisfying the cells' metabolic needs. Mitochondria are involved in calcium homeostasis and lipid metabolism, and they also regulate apoptotic processes. Many of these functions require contact with the ER, which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-ER contact sites (MERCS). Upon damage, mitochondria produce reactive oxygen species (ROS) that can harm the surrounding cell. To circumvent toxicity and to maintain a functional pool of healthy organelles, damaged and excess mitochondria can be targeted for degradation via mitophagy, a form of selective autophagy. Defects in mitochondria-ER tethers and the accumulation of damaged mitochondria are found in several neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, which argues that the interplay between the two organelles is vital for neuronal health. This review provides an overview of the different mechanisms of mitochondrial quality control that are implicated with the different mitochondria-ER tether proteins, and also provides a novel perspective on how MERCS are involved in mediating mitophagy upon mitochondrial damage.
Topics: Humans; Mitophagy; Mitochondria; Mitochondrial Membranes; Amyotrophic Lateral Sclerosis; Apoptosis; Mitochondrial Proteins; Receptors, Estrogen
PubMed: 37627263
DOI: 10.3390/biom13081198 -
Biology of the Cell Sep 2023Metabolism and mechanics are two key facets of structural and functional processes in cells, such as growth, proliferation, homeostasis and regeneration. Their... (Review)
Review
Metabolism and mechanics are two key facets of structural and functional processes in cells, such as growth, proliferation, homeostasis and regeneration. Their reciprocal regulation has been increasingly acknowledged in recent years: external physical and mechanical cues entail metabolic changes, which in return regulate cell mechanosensing and mechanotransduction. Since mitochondria are pivotal regulators of metabolism, we review here the reciprocal links between mitochondrial morphodynamics, mechanics and metabolism. Mitochondria are highly dynamic organelles which sense and integrate mechanical, physical and metabolic cues to adapt their morphology, the organization of their network and their metabolic functions. While some of the links between mitochondrial morphodynamics, mechanics and metabolism are already well established, others are still poorly documented and open new fields of research. First, cell metabolism is known to correlate with mitochondrial morphodynamics. For instance, mitochondrial fission, fusion and cristae remodeling allow the cell to fine-tune its energy production through the contribution of mitochondrial oxidative phosphorylation and cytosolic glycolysis. Second, mechanical cues and alterations in mitochondrial mechanical properties reshape and reorganize the mitochondrial network. Mitochondrial membrane tension emerges as a decisive physical property which regulates mitochondrial morphodynamics. However, the converse link hypothesizing a contribution of morphodynamics to mitochondria mechanics and/or mechanosensitivity has not yet been demonstrated. Third, we highlight that mitochondrial mechanics and metabolism are reciprocally regulated, although little is known about the mechanical adaptation of mitochondria in response to metabolic cues. Deciphering the links between mitochondrial morphodynamics, mechanics and metabolism still presents significant technical and conceptual challenges but is crucial both for a better understanding of mechanobiology and for potential novel therapeutic approaches in diseases such as cancer.
Topics: Mechanotransduction, Cellular; Mitochondria; Mitochondrial Membranes; Organelles; Biophysics; Mitochondrial Dynamics
PubMed: 37326132
DOI: 10.1111/boc.202300010 -
Cell Reports Dec 2023Mitochondria are dynamic organelles that undergo fusion and fission events, in which the mitochondrial membrane and DNA (mtDNA) play critical roles. The spatiotemporal...
Mitochondria are dynamic organelles that undergo fusion and fission events, in which the mitochondrial membrane and DNA (mtDNA) play critical roles. The spatiotemporal organization of mtDNA reflects and impacts mitochondrial dynamics. Herein, to study the detailed dynamics of mitochondrial membrane and mtDNA, we rationally develop a dual-color fluorescent probe, mtGLP, that could be used for simultaneously monitoring mitochondrial membrane and mtDNA dynamics via separate color outputs. By combining mtGLP with structured illumination microscopy to monitor mitochondrial dynamics, we discover the formation of nucleoid condensates in damaged mitochondria. We further reveal that nucleoid condensates promoted the peripheral fission of damaged mitochondria via asymmetric segregation. Through simulations, we find that the peripheral fission events occurred when the nucleoid condensates interacted with the highly curved membrane regions at the two ends of the mitochondria. Overall, we show that mitochondrial nucleoid condensates utilize peripheral fission to maintain mitochondrial homeostasis.
Topics: Mitochondria; DNA, Mitochondrial; Mitochondrial Membranes; Mitochondrial Dynamics; Mitochondrial Proteins
PubMed: 37999975
DOI: 10.1016/j.celrep.2023.113472 -
Antioxidants & Redox Signaling Oct 2023Mitochondrial (mt) reticulum network in the cell possesses amazing ultramorphology of parallel lamellar cristae, formed by the invaginated inner mitochondrial membrane.... (Review)
Review
Mitochondrial (mt) reticulum network in the cell possesses amazing ultramorphology of parallel lamellar cristae, formed by the invaginated inner mitochondrial membrane. Its non-invaginated part, the inner boundary membrane (IBM) forms a cylindrical sandwich with the outer mitochondrial membrane (OMM). Crista membranes (CMs) meet IBM at crista junctions (CJs) of mt cristae organizing system (MICOS) complexes connected to OMM sorting and assembly machinery (SAM). Cristae dimensions, shape, and CJs have characteristic patterns for different metabolic regimes, physiological and pathological situations. Cristae-shaping proteins were characterized, namely rows of ATP-synthase dimers forming the crista lamella edges, MICOS subunits, optic atrophy 1 (OPA1) isoforms and mitochondrial genome maintenance 1 (MGM1) filaments, prohibitins, and others. Detailed cristae ultramorphology changes were imaged by focused-ion beam/scanning electron microscopy. Dynamics of crista lamellae and mobile CJs were demonstrated by nanoscopy in living cells. With tBID-induced apoptosis a single entirely fused cristae reticulum was observed in a mitochondrial spheroid. The mobility and composition of MICOS, OPA1, and ATP-synthase dimeric rows regulated by post-translational modifications might be exclusively responsible for cristae morphology changes, but ion fluxes across CM and resulting osmotic forces might be also involved. Inevitably, cristae ultramorphology should reflect also mitochondrial redox homeostasis, but details are unknown. Disordered cristae typically reflect higher superoxide formation. To link redox homeostasis to cristae ultramorphology and define markers, recent progress will help in uncovering mechanisms involved in proton-coupled electron transfer the respiratory chain and in regulation of cristae architecture, leading to structural determination of superoxide formation sites and cristae ultramorphology changes in diseases. 39, 635-683.
Topics: Mitochondrial Membranes; Superoxides; Homeostasis; Oxidation-Reduction; Adenosine Triphosphate; Mitochondrial Proteins
PubMed: 36793196
DOI: 10.1089/ars.2022.0173 -
Discovery Medicine Oct 2023Mitochondria-associated membranes (MAMs) play a significant role in multiple cellular processes including lipid metabolism and neuronal survival. Fatty acids constitute... (Review)
Review
Mitochondria-associated membranes (MAMs) play a significant role in multiple cellular processes including lipid metabolism and neuronal survival. Fatty acids constitute 80% of the dry mass of the brain and are vital for life. Apart from mitochondrial β-oxidation, fatty acids are metabolized in part by peroxisomes to regulate the generation of acyl Coenzyme A and adenosine triphosphate (ATP). Ablation of mitochondria and its associated genes tether endoplasmic reticulum (ER)-Mitochondria contact and results in loss of function leading to aberrant lipid metabolism. Additionally, an increase in reactive oxygen species (ROS) levels along with free radicals' generation may lead to alteration in the integrity of membrane phospholipids, proteins, and DNA. Hence, it is critical to understand the effect of structural and functional aspects of mitochondria on lipid homeostasis. This review explains the role of mitochondrial dysfunction in lipid metabolism and its impact on various neurodegenerative diseases and metabolic disorders.
Topics: Humans; Mitochondria; Reactive Oxygen Species; Homeostasis; Fatty Acids; Lipids
PubMed: 37811607
DOI: 10.24976/Discov.Med.202335178.64 -
Journal of Cell Science Jan 2024Mitochondria are multifunctional organelles of key importance for cell homeostasis. The outer mitochondrial membrane (OMM) envelops the organelle, and the inner... (Review)
Review
Mitochondria are multifunctional organelles of key importance for cell homeostasis. The outer mitochondrial membrane (OMM) envelops the organelle, and the inner mitochondrial membrane (IMM) is folded into invaginations called cristae. As cristae composition and functions depend on the cell type and stress conditions, they recently started to be considered as a dynamic compartment. A number of proteins are known to play a role in cristae architecture, such as OPA1, MIC60, LETM1, the prohibitin (PHB) complex and the F1FO ATP synthase. Furthermore, phospholipids are involved in the maintenance of cristae ultrastructure and dynamics. The use of new technologies, including super-resolution microscopy to visualize cristae dynamics with superior spatiotemporal resolution, as well as high-content techniques and datasets have not only allowed the identification of new cristae proteins but also helped to explore cristae plasticity. However, a number of open questions remain in the field, such as whether cristae-resident proteins are capable of changing localization within mitochondria, or whether mitochondrial proteins can exit mitochondria through export. In this Review, we present the current view on cristae morphology, stability and composition, and address important outstanding issues that might pave the way to future discoveries.
Topics: Mitochondria; Mitochondrial Membranes; Microscopy; Mitochondrial Proteins; Phospholipids
PubMed: 38197774
DOI: 10.1242/jcs.260986 -
Protein Expression and Purification Oct 2023The protein Family with sequence similarity 210 member A (FAM210A) is a mitochondrial inner membrane protein that regulates the protein synthesis of mitochondrial DNA...
The protein Family with sequence similarity 210 member A (FAM210A) is a mitochondrial inner membrane protein that regulates the protein synthesis of mitochondrial DNA encoded genes. However, how it functions in this process is not well understood. Developing and optimizing a protein purification strategy will facilitate biochemical and structural studies of FAM210A. Here, we developed a method to purify human FAM210A with deleted mitochondrial targeting signal sequence using the MBP-His fusion in Escherichia coli. The recombinant FAM210A protein was inserted into the E. coli cell membrane and purified from isolated bacterial cell membranes, followed by a two-step process using Ni-NTA resin-based immobilized-metal affinity chromatography (IMAC) and ion exchange purification. A pulldown assay validated the functionality of purified FAM210A protein interacting with human mitochondrial elongation factor EF-Tu in HEK293T cell lysates. Taken together, this study developed a method for purification of the mitochondrial transmembrane protein FAM210A partially complexed with E.coli derived EF-Tu and provides an opportunity for future potential biochemical and structural studies of recombinant FAM210A protein.
Topics: Humans; Escherichia coli; Peptide Elongation Factor Tu; Mitochondrial Proteins; HEK293 Cells; Recombinant Proteins; Membrane Proteins
PubMed: 37329934
DOI: 10.1016/j.pep.2023.106322 -
Journal of Cellular Physiology Aug 2023Kidney diseases are serious health problems affecting >800 million individuals worldwide. The high number of affected individuals and the severe consequences of kidney... (Review)
Review
Kidney diseases are serious health problems affecting >800 million individuals worldwide. The high number of affected individuals and the severe consequences of kidney dysfunction demand an intensified effort toward more effective prevention and treatment. The pathophysiology of kidney diseases is complex and comprises diverse organelle dysfunctions including mitochondria and endoplasmic reticulum (ER). The recent findings prove interactions between the ER membrane and nearly all cell compartments and give new insights into molecular events involved in cellular mechanisms in health and disease. Interactions between the ER and mitochondrial membranes, known as the mitochondria-ER contacts regulate kidney physiology by interacting with each other via membrane contact sites (MCS). ER controls mitochondrial dynamics through ER stress sensor proteins or by direct communication via mitochondria-associated ER membrane to activate signaling pathways such as apoptosis, calcium transport, and autophagy. More importantly, these organelle dynamics are found to be regulated by several epigenetic mechanisms such as DNA methylation, histone modifications, and noncoding RNAs and can be a potential therapeutic target against kidney diseases. However, a thorough understanding of the role of epigenetic regulation of organelle dynamics and their functions is not well understood. Therefore, this review will unveil the role of epigenetic mechanisms in regulating organelle dynamics during various types of kidney diseases. Moreover, we will also shed light on different stress origins in organelles leading to kidney disease. Henceforth, by understanding this we can target epigenetic mechanisms to maintain/control organelle dynamics and serve them as a novel therapeutic approach against kidney diseases.
Topics: Humans; Mitochondrial Dynamics; Epigenesis, Genetic; Endoplasmic Reticulum; Mitochondria; Kidney Diseases; Endoplasmic Reticulum Stress
PubMed: 37357431
DOI: 10.1002/jcp.31058 -
Journal of Theoretical Biology Aug 2023Recent studies delineate an intimate crosstalk between apoptosis and inflammation. However, the dynamic mechanism linking them by mitochondrial membrane permeabilization...
Recent studies delineate an intimate crosstalk between apoptosis and inflammation. However, the dynamic mechanism linking them by mitochondrial membrane permeabilization remains elusive. Here, we construct a mathematical model consisting of four functional modules. Bifurcation analysis reveals that bistability stems from Bcl-2 family member interaction and time series shows that the time difference between Cyt c and mtDNA release is around 30 min, which are consistent with previous works. The model predicts that Bax aggregation kinetic determines cells to undergo apoptosis or inflammation, and that modulating the inhibitory effect of caspase 3 on IFN-β production allows the concurrent occurrence of apoptosis and inflammation. This work provides a theoretical framework for exploring the mechanism of mitochondrial membrane permeabilization in controlling cell fate.
Topics: Humans; Mitochondrial Membranes; bcl-2-Associated X Protein; Mitochondria; Apoptosis; Inflammation
PubMed: 37327862
DOI: 10.1016/j.jtbi.2023.111558 -
Experimental Cell Research Oct 2023Organelles are dynamic entities whose functions are essential for the optimum functioning of cells. It is now known that the juxtaposition of organellar membranes is... (Review)
Review
Organelles are dynamic entities whose functions are essential for the optimum functioning of cells. It is now known that the juxtaposition of organellar membranes is essential for the exchange of metabolites and their communication. These functional apposition sites are termed membrane contact sites. Dynamic membrane contact sites between various sub-cellular structures such as mitochondria, endoplasmic reticulum, peroxisomes, Golgi apparatus, lysosomes, lipid droplets, plasma membrane, endosomes, etc. have been reported in various model systems. The burgeoning area of research on membrane contact sites has witnessed several manuscripts in recent years that identified the contact sites and components involved. Several methods have been developed to identify, measure and analyze the membrane contact sites. In this manuscript, we aim to discuss important methods developed to date that are used to study membrane contact sites.
Topics: Mitochondrial Membranes; Mitochondria; Cell Membrane; Endoplasmic Reticulum; Endosomes
PubMed: 37633408
DOI: 10.1016/j.yexcr.2023.113756