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Mitochondrion Jul 2023As the cell's energy factory and metabolic hub, mitochondria are critical for ATP synthesis to maintain cellular function. Mitochondria are highly dynamic organelles... (Review)
Review
As the cell's energy factory and metabolic hub, mitochondria are critical for ATP synthesis to maintain cellular function. Mitochondria are highly dynamic organelles that continuously undergo fusion and fission to alter their size, shape, and position, with mitochondrial fusion and fission being interdependent to maintain the balance of mitochondrial morphological changes. However, in response to metabolic and functional damage, mitochondria can grow in size, resulting in a form of abnormal mitochondrial morphology known as megamitochondria. Megamitochondria are characterized by their considerably larger size, pale matrix, and marginal cristae structure and have been observed in various human diseases. In energy-intensive cells like hepatocytes or cardiomyocytes, the pathological process can lead to the growth of megamitochondria, which can further cause metabolic disorders, cell damage and aggravates the progression of the disease. Nonetheless, megamitochondria can also form in response to short-term environmental stimulation as a compensatory mechanism to support cell survival. However, extended stimulation can reverse the benefits of megamitochondria leading to adverse effects. In this review, we will focus on the findings of the different roles of megamitochondria, and their link to disease development to identify promising clinical therapeutic targets.
Topics: Humans; Mitochondrial Swelling; Mitochondria; Metabolic Diseases; Hepatocytes; Mitochondrial Membranes; Mitochondrial Dynamics
PubMed: 37276954
DOI: 10.1016/j.mito.2023.06.001 -
European Journal of Biochemistry Feb 2004Mitochondrial beta-oxidation is a complex pathway involving, in the case of saturated straight chain fatty acids of even carbon number, at least 16 proteins which are... (Review)
Review
Mitochondrial beta-oxidation is a complex pathway involving, in the case of saturated straight chain fatty acids of even carbon number, at least 16 proteins which are organized into two functional subdomains; one associated with the inner face of the inner mitochondrial membrane and the other in the matrix. Overall, the pathway is subject to intramitochondrial control at multiple sites. However, at least in the liver, carnitine palmitoyl transferase I exerts approximately 80% of control over pathway flux under normal conditions. Clearly, when one or more enzyme activities are attenuated because of a mutation, the major site of flux control will change.
Topics: Animals; Fasting; Mitochondria; Organ Specificity; Oxidation-Reduction; Stress, Physiological
PubMed: 14728673
DOI: 10.1046/j.1432-1033.2003.03947.x -
The FEBS Journal Nov 2022Electron transport chain (ETC) dysfunction is a common feature of mitochondrial diseases and induces severe cellular stresses, including mitochondrial membrane potential... (Review)
Review
Electron transport chain (ETC) dysfunction is a common feature of mitochondrial diseases and induces severe cellular stresses, including mitochondrial membrane potential (Δψ ) reduction, mitochondrial matrix acidification, metabolic derangements and proteostatic stresses. Extensive studies of ETC dysfunction in yeast, Caenorhabditis elegans, cultured cells and mouse models have revealed multiple mitochondrial stress response pathways. Here, we summarise the current understanding of the triggers, sensors, signalling mechanisms and the functional outcomes of mitochondrial stress responses in different species. We highlight Δψ reduction as a major trigger of stress responses in different species, but the responses are species-specific and the outcomes are context-dependent. ETC dysfunction elicits a mitochondrial unfolded protein response (UPR ) to repair damaged mitochondria in C. elegans, and activates a global adaptive programme to maintain Δψ in yeast. Yeast and C. elegans responses are remarkably similar at the downstream responses, although they are activated by different signalling mechanisms. UPR generally protects ETC-defective worms, but its constitutive activation is toxic for wildtype worms and worms carrying mutant mtDNA. In contrast to lower organisms, ETC dysfunction in mammals mainly activates a mitochondrial integrated stress response (ISR ) to reprogramme metabolism and a PINK1-Parkin mitophagy pathway to degrade damaged mitochondria. Accumulating in vivo results suggest that the ATF4 branch of ISR exacerbates metabolic derangements to accelerate mitochondrial disease progression. The in vivo roles of mitophagy in mitochondrial diseases are also context-dependent. These results thus reveal the common and unique aspects of mitochondrial stress responses in different species and highlight their multifaceted roles in mitochondrial diseases.
Topics: Animals; Mice; Caenorhabditis elegans; Saccharomyces cerevisiae; Mitochondria; Mitophagy; Unfolded Protein Response; Mammals
PubMed: 34918460
DOI: 10.1111/febs.16323 -
Cell Biology and Toxicology Apr 2023Mitochondrial metabolism and function are modulated by changes in matrix Ca. Small increases in the matrix Ca stimulate mitochondrial bioenergetics, whereas excessive Ca...
Mitochondrial metabolism and function are modulated by changes in matrix Ca. Small increases in the matrix Ca stimulate mitochondrial bioenergetics, whereas excessive Ca leads to cell death by causing massive matrix swelling and impairing the structural and functional integrity of mitochondria. Sustained opening of the non-selective mitochondrial permeability transition pores (PTP) is the main mechanism responsible for mitochondrial Ca overload that leads to mitochondrial dysfunction and cell death. Recent studies suggest the existence of two or more types of PTP, and adenine nucleotide translocator (ANT) and FF-ATP synthase were proposed to form the PTP independent of each other. Here, we elucidated the role of ANT in PTP opening by applying both experimental and computational approaches. We first developed and corroborated a detailed model of the ANT transport mechanism including the matrix (ANT), cytosolic (ANT), and pore (ANT) states of the transporter. Then, the ANT model was incorporated into a simple, yet effective, empirical model of mitochondrial bioenergetics to ascertain the point when Ca overload initiates PTP opening via an ANT switch-like mechanism activated by matrix Ca and is inhibited by extra-mitochondrial ADP. We found that encoding a heterogeneous Ca response of at least three types of PTPs, weakly, moderately, and strongly sensitive to Ca, enabled the model to simulate Ca release dynamics observed after large boluses were administered to a population of energized cardiac mitochondria. Thus, this study demonstrates the potential role of ANT in PTP gating and proposes a novel mechanism governing the cryptic nature of the PTP phenomenon.
Topics: Mitochondrial Membrane Transport Proteins; Adenine Nucleotides; Mitochondrial Swelling; Mitochondria; Mitochondrial Permeability Transition Pore; Calcium
PubMed: 35606662
DOI: 10.1007/s10565-022-09724-2 -
Journal of Cell Science May 2021Myosin XIX (Myo19) is an actin-based motor that competes with adaptors of microtubule-based motors for binding to the outer mitochondrial transmembrane proteins Miro1...
Myosin XIX (Myo19) is an actin-based motor that competes with adaptors of microtubule-based motors for binding to the outer mitochondrial transmembrane proteins Miro1 and Miro2 (collectively Miro, also known as RhoT1 and RhoT2, respectively). Here, we investigate which mitochondrial and cellular processes depend on the coordination of Myo19 and microtubule-based motor activities. To this end, we created Myo19-deficient HEK293T cells. Mitochondria in these cells were not properly fragmented at mitosis and were partitioned asymmetrically to daughter cells. Respiratory functions of mitochondria were impaired and ROS generation was enhanced. On a cellular level, cell proliferation, cytokinesis and cell-matrix adhesion were negatively affected. On a molecular level, Myo19 regulates focal adhesions in interphase, and mitochondrial fusion and mitochondrially associated levels of fission protein Drp1 and adaptor proteins dynactin and TRAK1 at prometaphase. These alterations were due to a disturbed coordination of Myo19 and microtubule-based motor activities by Miro.
Topics: Actins; HEK293 Cells; Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins; Myosins; rho GTP-Binding Proteins
PubMed: 34013964
DOI: 10.1242/jcs.255844 -
Proceedings of the National Academy of... May 2022Primary mitochondrial diseases (PMDs) are a heterogeneous group of metabolic disorders that can be caused by hundreds of mutations in both mitochondrial DNA (mtDNA) and...
Primary mitochondrial diseases (PMDs) are a heterogeneous group of metabolic disorders that can be caused by hundreds of mutations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes. Current therapeutic approaches are limited, although one approach has been exercise training. Endurance exercise is known to improve mitochondrial function in heathy subjects and reduce risk for secondary metabolic disorders such as diabetes or neurodegenerative disorders. However, in PMDs the benefit of endurance exercise is unclear, and exercise might be beneficial for some mitochondrial disorders but contraindicated in others. Here we investigate the effect of an endurance exercise regimen in mouse models for PMDs harboring distinct mitochondrial mutations. We show that while an mtDNA ND6 mutation in complex I demonstrated improvement in response to exercise, mice with a CO1 mutation affecting complex IV showed significantly fewer positive effects, and mice with an ND5 complex I mutation did not respond to exercise at all. For mice deficient in the nDNA adenine nucleotide translocase 1 (Ant1), endurance exercise actually worsened the dilated cardiomyopathy. Correlating the gene expression profile of skeletal muscle and heart with the physiologic exercise response identified oxidative phosphorylation, amino acid metabolism, matrisome (extracellular matrix [ECM]) structure, and cell cycle regulation as key pathways in the exercise response. This emphasizes the crucial role of mitochondria in determining the exercise capacity and exercise response. Consequently, the benefit of endurance exercise in PMDs strongly depends on the underlying mutation, although our results suggest a general beneficial effect.
Topics: Animals; Humans; Mice; Mitochondria; Mitochondrial Diseases; Mutation; Physical Conditioning, Animal; Physical Endurance
PubMed: 35482926
DOI: 10.1073/pnas.2200549119 -
The EMBO Journal Apr 2023Macromolecules of various sizes induce crowding of the cellular environment. This crowding impacts on biochemical reactions by increasing solvent viscosity, decreasing...
Macromolecules of various sizes induce crowding of the cellular environment. This crowding impacts on biochemical reactions by increasing solvent viscosity, decreasing the water-accessible volume and altering protein shape, function, and interactions. Although mitochondria represent highly protein-rich organelles, most of these proteins are somehow immobilized. Therefore, whether the mitochondrial matrix solvent exhibits macromolecular crowding is still unclear. Here, we demonstrate that fluorescent protein fusion peptides (AcGFP1 concatemers) in the mitochondrial matrix of HeLa cells display an elongated molecular structure and that their diffusion constant decreases with increasing molecular weight in a manner typical of macromolecular crowding. Chloramphenicol (CAP) treatment impaired mitochondrial function and reduced the number of cristae without triggering mitochondrial orthodox-to-condensed transition or a mitochondrial unfolded protein response. CAP-treated cells displayed progressive concatemer immobilization with increasing molecular weight and an eightfold matrix viscosity increase, compatible with increased macromolecular crowding. These results establish that the matrix solvent exhibits macromolecular crowding in functional and dysfunctional mitochondria. Therefore, changes in matrix crowding likely affect matrix biochemical reactions in a manner depending on the molecular weight of the involved crowders and reactants.
Topics: Humans; HeLa Cells; Macromolecular Substances; Proteins; Solvents; Mitochondria
PubMed: 36825437
DOI: 10.15252/embj.2021108533 -
Biochemical Society Transactions Aug 2019Among several theories to explain the complicated process of human ageing, the mitochondrial oxidative stress hypothesis has received recent attention. Considering that... (Review)
Review
Among several theories to explain the complicated process of human ageing, the mitochondrial oxidative stress hypothesis has received recent attention. Considering that lifespan and ageing rates vary considerably across taxa, a better understanding of factors that lead to negligible or extremely rapid senescence in mammals may generate novel approaches to target human ageing. Several species, such as naked mole rats, ocean quahog, rockfish and Greenland shark, have been identified that exhibit negligible senescence and superior resistance to age-related diseases. Considering that the available literature suggests that their outstanding stress resistance is linked to maintenance of protein homeostasis and robust mitochondrial functions, treatments that target protein modification and upregulation of matrix antioxidants may have implications for extending human health span.
Topics: Aging; Animals; Free Radicals; Homeostasis; Humans; Longevity; Mitochondria; Oxidative Stress
PubMed: 31366472
DOI: 10.1042/BST20190105 -
Mitochondrion Jan 2018Mitochondria are critical players involved in both cell life and death through multiple pathways. Structural integrity, metabolism and function of mitochondria are... (Review)
Review
Mitochondria are critical players involved in both cell life and death through multiple pathways. Structural integrity, metabolism and function of mitochondria are regulated by matrix volume due to physiological changes of ion homeostasis in cellular cytoplasm and mitochondria. Ca and K presumably play a critical role in physiological and pathological swelling of mitochondria when increased uptake (influx)/decreased release (efflux) of these ions enhances osmotic pressure accompanied by high water accumulation in the matrix. Changes in the matrix volume in the physiological range have a stimulatory effect on electron transfer chain and oxidative phosphorylation to satisfy metabolic requirements of the cell. However, excessive matrix swelling associated with the sustained opening of mitochondrial permeability transition pores (PTP) and other PTP-independent mechanisms compromises mitochondrial function and integrity leading to cell death. The mechanisms of transition from reversible (physiological) to irreversible (pathological) swelling of mitochondria remain unknown. Mitochondrial swelling is involved in the pathogenesis of many human diseases such as neurodegenerative and cardiovascular diseases. Therefore, modeling analysis of the swelling process is important for understanding the mechanisms of cell dysfunction. This review attempts to describe the role of mitochondrial swelling in cell life and death and the main mechanisms involved in the maintenance of ion homeostasis and swelling. The review also summarizes and discusses different kinetic models and approaches that can be useful for the development of new models for better simulation and prediction of in vivo mitochondrial swelling.
Topics: Cardiovascular Diseases; Electron Transport; Humans; Mitochondria; Mitochondrial Membranes; Mitochondrial Swelling; Models, Biological; Neurodegenerative Diseases; Osmotic Pressure; Oxidative Phosphorylation; Permeability
PubMed: 28802667
DOI: 10.1016/j.mito.2017.08.004 -
Best Practice & Research. Clinical... Dec 2012Mitochondria are membrane bound organelles present in almost all eukaryotic cells. Responsible for orchestrating cellular energy production, they are central to the... (Review)
Review
Mitochondria are membrane bound organelles present in almost all eukaryotic cells. Responsible for orchestrating cellular energy production, they are central to the maintenance of life and the gatekeepers of cell death. Thought to have originated from symbiotic ancestors, they carry a residual genome as mtDNA encoding 13 proteins essential for respiratory chain function. Mitochondria comprise an inner and outer membrane that separate and maintain the aqueous regions, the intermembrane space and the matrix. Mitochondria contribute to many processes central to cellular function and dysfunction including calcium signalling, cell growth and differentiation, cell cycle control and cell death. Mitochondrial shape and positioning in cells is crucial and is tightly regulated by processes of fission and fusion, biogenesis and autophagy, ensuring a relatively constant mitochondrial population. Mitochondrial dysfunction is implicated in metabolic and age related disorders, neurodegenerative diseases and ischemic injury in heart and brain.
Topics: Animals; Calcium Signaling; Cell Death; Citric Acid Cycle; Energy Metabolism; Humans; Mitochondria
PubMed: 23168274
DOI: 10.1016/j.beem.2012.05.003