Explore the vast range of titles available.

Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.

Currently, it is known that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. It is also known that mitochondria, because of their capacity to produce free radicals, play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including the stimulation of permeability transition pore opening. This process leads to mitoptosis and mitophagy, two sequential processes that are a universal route of elimination of dysfunctional mitochondria and is essential to protect cells from the harm due to mitochondrial disordered metabolism. To date, there is significant evidence not only that the above processes are induced by enhanced reactive oxygen species (ROS) production, but also that such production is involved in the other phases of the mitochondrial life cycle. Accumulating evidence also suggests that these effects are mediated through the regulation of the expression and the activity of proteins that are engaged in processes such as genesis, fission, fusion, and removal of mitochondria. This review provides an account of the developments of the knowledge on the dynamics of the mitochondrial population, examining the mechanisms governing their genesis, life, and death, and elucidating the role played by free radicals in such processes.

Mitochondrial dynamics is an essential physiological process controlling mitochondrial content mixing and mobility to ensure proper function and localization of mitochondria at intracellular sites of high-energy demand. Intriguingly, for yet unknown reasons, severe impairment of mitochondrial fusion drastically affects mtDNA copy number. To decipher the link between mitochondrial dynamics and mtDNA maintenance, we studied mouse embryonic fibroblasts (MEFs) and mouse cardiomyocytes with disruption of mitochondrial fusion. Super-resolution microscopy revealed that loss of outer mitochondrial membrane (OMM) fusion, but not inner mitochondrial membrane (IMM) fusion, leads to nucleoid clustering. Remarkably, fluorescence in situ hybridization (FISH), bromouridine labeling in MEFs and assessment of mitochondrial transcription in tissue homogenates revealed that abolished OMM fusion does not affect transcription. Furthermore, the profound mtDNA depletion in mouse hearts lacking OMM fusion is not caused by defective integrity or increased mutagenesis of mtDNA, but instead we show that mitochondrial fusion is necessary to maintain the stoichiometry of the protein components of the mtDNA replisome. OMM fusion is necessary for proliferating MEFs to recover from mtDNA depletion and for the marked increase of mtDNA copy number during postnatal heart development. Our findings thus link OMM fusion to replication and distribution of mtDNA.

Mitochondrial dynamics are balanced fission and fusion events that regulate mitochondrial morphology, and alteration in these events results in mitochondrial dysfunction and contributes to many diseases, including tumorigenesis. Ovarian cancer (OC) cells exhibit fragmented mitochondria, but the mechanism by which mitochondrial dynamics regulators contribute to OC is considerably less clear. Here, we elucidated the potential role of Mfn2-mediated mitochondrial fusion in OC and present evidence that genetic or pharmacological activation of Mfn2 leads to mitochondrial fusion and reduces ROS generation, which correlates with reduced cell proliferation, invasion, migration, and EMT in OC cells. Also, increased mitochondrial fusion promotes the F-actin remodeling, reduces lamellipodia formation, and thus reduces EMT. Increased expression of Mfn2 triggers AMPK, promotes autophagy, reduces ROS, and suppresses OC progression by downregulating  the p-mTOR (2481 and 2448) and p-ERK axis. OC patients with higher Mfn2 expression have better survival than those with lower Mfn2 levels. Our findings demonstrate that restoration of Mfn2-mediated mitochondrial fusion suppressed OC progression and suggest that this process could be a potential strategy in OC treatment.

Mitochondria are essential components of eukaryotic cells, carrying out critical physiological processes that include energy production and calcium buffering. Consequently, mitochondrial dysfunction is associated with a range of human diseases. Fundamental to their function is the ability to transition through fission and fusion states, which is regulated by several GTPases. Here, we have developed new methods for the non-subjective quantification of mitochondrial morphology in muscle and neuronal cells of Caenorhabditis elegans . Using these techniques, we uncover surprising tissue-specific differences in mitochondrial morphology when fusion or fission proteins are absent. From ultrastructural analysis, we reveal a novel role for the fusion protein FZO-1/mitofusin 2 in regulating the structure of the inner mitochondrial membrane. Moreover, we have determined the influence of the individual mitochondrial fission (DRP-1/DRP1) and fusion (FZO-1/mitofusin 1,2; EAT-3/OPA1) proteins on animal behaviour and lifespan. We show that loss of these mitochondrial fusion or fission regulators induced age-dependent and progressive deficits in animal movement, as well as in muscle and neuronal function. Our results reveal that disruption of fusion induces more profound defects than lack of fission on animal behaviour and tissue function, and imply that while fusion is required throughout life, fission is more important later in life likely to combat ageing-associated stressors. Furthermore, our data demonstrate that mitochondrial function is not strictly dependent on morphology, with no correlation found between morphological changes and behavioural defects. Surprisingly, we find that disruption of either mitochondrial fission or fusion significantly reduces median lifespan, but maximal lifespan is unchanged, demonstrating that mitochondrial dynamics play an important role in limiting variance in longevity across isogenic populations. Overall, our study provides important new insights into the central role of mitochondrial dynamics in maintaining organismal health.

Mitochondria have their own DNA (mtDNA), which encodes essential respiratory subunits. Under live imaging, mitochondrial nucleoids, composed of several copies of mtDNA and DNA-binding proteins, such as mitochondrial transcription factor A (TFAM), actively move inside mitochondria and change the morphology, in concert with mitochondrial membrane fission. Here we found the mitochondrial inner membraneanchored AAA-ATPase protein ATAD3A mediates the nucleoid dynamics. Its ATPase domain exposed to the matrix binds directly to TFAM and mediates nucleoid trafficking along mitochondria by ATP hydrolysis. Nucleoid trafficking also required ATAD3A oligomerization via an interaction between the coiled-coil domains in intermembrane space. In ATAD3A deficiency, impaired nucleoid trafficking repressed the clustered and enlarged nucleoids observed in mitochondrial fission-deficient cells resulted in dispersed distribution of small nucleoids observed throughout the mitochondrial network, and this enhanced respiratory complex formation. Thus, mitochondrial fission and nucleoid trafficking cooperatively determine the size, number, and distribution of nucleoids in mitochondrial network, which should modulate respiratory complex formation.

Mitochondria are vital cellular organelles involved in a plethora of cellular processes such as energy conversion, calcium homeostasis, heme biogenesis, regulation of apoptosis and ROS reactive oxygen species (ROS) production. Although they are frequently depicted as static bean-shaped structures, our view has markedly changed over the past few decades as many studies have revealed a remarkable dynamicity of mitochondrial shapes and sizes both at the cellular and intra-mitochondrial levels. Aberrant changes in mitochondrial dynamics and cristae structure are associated with ageing and numerous human diseases (e.g., cancer, diabetes, various neurodegenerative diseases, types of neuro- and myopathies). Another unique feature of mitochondria is that they harbor their own genome, the mitochondrial DNA (mtDNA). MtDNA exists in several hundreds to thousands of copies per cell and is arranged and packaged in the mitochondrial matrix in structures termed mt-nucleoids. Many human diseases are mechanistically linked to mitochondrial dysfunction and alteration of the number and/or the integrity of mtDNA. In particular, several recent studies identified remarkable and partly unexpected links between mitochondrial structure, fusion and fission dynamics, and mtDNA. In this review, we will provide an overview about these recent insights and aim to clarify how mitochondrial dynamics, cristae ultrastructure and mtDNA structure influence each other and determine mitochondrial functions.

Human triple negative breast cancer cells, MDA-MB-231, show typical epithelial to mesenchymal transition associated with cancer progression. Mitochondria play a major role in cancer progression, including metastasis. Changes in mitochondrial architecture affect cellular migration, autophagy and apoptosis. Silibinin is reported to have anti-breast cancer effect. We here report that silibinin at lower concentrations (30–90 μM) inhibits epithelial to mesenchymal transition (EMT) of MDA-MB-231, by increasing the expression of epithelial marker, E-cadherin, and decreasing the expression of mesenchymal markers, N-cadherin and vimentin. Besides, silibinin inhibition of cell migration is associated with reduction in the protein expression of matrix metalloproteinases 2 and 9 (MMP2 and MMP9) and paxillin. In addition, silibinin treatment increases mitochondrial fusion through down-regulating the expression of mitochondrial fission-associated protein dynamin-related protein 1 (DRP1) and up-regulating the expression of mitochondrial fusion-associated proteins, optic atrophy 1, mitofusin 1 and mitofusin 2. Silibinin perturbed mitochondrial biogenesis via down-regulating the levels of mitochondrial biogenesis regulators including mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor gamma coactivator (PGC1) and nuclear respiratory factor (NRF2). Moreover, DRP1 knockdown or silibinin inhibited cell migration, and MFN1&2 knockdown restored it. Mitochondrial fusion contributes to silibinin’s negative effect on cell migration. Silibinin decreased reactive oxygen species (ROS) generation, leading to inhibition of the NLRP3 inflammasome activation. In addition, knockdown of mitofusin 1&2 (MFN 1&2) relieved silibinin-induced inhibition of NLRP3 inflammasome activation. Repression of ROS contributes to the inhibition of the expression of NLRP3, caspase-1 and IL-β proteins as well as of cell migration. Taken together, our study provides evidence that silibinin impairs mitochondrial dynamics and biogenesis, resulting in reduced migration and invasion of the MDA-MB-231 breast cancer cells.

Mitochondrial diseases are a complex and clinically heterogeneous group of disorders, which— together with our poor understanding of the underlying pathology—makes their diagnosis difficult. Here, DiMauro et al . review current knowledge of defects of the mitochondrial respiratory complex that lead to neurological mitochondrial disorders, outlining diagnostic clues for each disorder, and discussing current therapeutic approaches for these often devastating diseases. Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and mitochondrial DNA (mtDNA). The complexity of mitochondrial genetics provides one explanation for the clinical heterogeneity of mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical mitochondrial disease phenotypes. Mendelian mitochondrial defects can affect five components of mitochondrial biology: subunits of respiratory chain complexes (direct hits); mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner mitochondrial membrane; or mitochondrial dynamics. A sixth category—defects of mtDNA maintenance—combines features of Mendelian and mitochondrial genetics. Genetic defects in mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot–Marie–Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the genetics and pathogenesis of the six categories of mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of mitochondrial disease, as well as potential therapeutic strategies, is also discussed. Key Points Few neurological disorders are as phenotypically heterogeneous and diagnostically challenging as mitochondrial encephalomyopathies The clinical heterogeneity of mitochondrial disorders can be explained by both the unique rules of mitochondrial genetics and the dependence of most mitochondrial functions on a wide variety of nuclear genes Despite advances in understanding the molecular aetiology of mitochondrial diseases, their pathogenesis is still largely unknown Through whole-exome or mito-exome sequencing, novel mutant genes and novel disease mechanisms of mitochondrial disease are being revealed Promising areas of investigation for neurological mitochondria-associated disorders include defects in lipid composition of the mitochondrial membrane and defects of the mitochondria-associated membrane

Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signaling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signaling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative disorders.