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Non-exudative age-related macular degeneration (NE-AMD) is the leading blindness cause in the elderly. Clinical and experimental evidence supports that early alterations in macular retinal pigment epithelium (RPE) mitochondria play a key role in NE-AMD-induced damage. Mitochondrial dynamics (biogenesis, fusion, fission, and mitophagy), which is under the central control of AMP-activated kinase (AMPK), in turn, determines mitochondrial quality. We have developed a NE-AMD model in C57BL/6J mice induced by unilateral superior cervical ganglionectomy (SCGx), which progressively reproduces the disease hallmarks circumscribed to the temporal region of the RPE/outer retina that exhibits several characteristics of the human macula. In this work we have studied RPE mitochondrial structure, dynamics, function, and AMPK role on these parameters' regulation at the nasal and temporal RPE from control eyes and at an early stage of experimental NE-AMD (i.e., 4 weeks post-SCGx). Although RPE mitochondrial mass was preserved, their function, which was higher at the temporal than at the nasal RPE in control eyes, was significantly decreased at 4 weeks post-SCGx at the same region. Mitochondria were bigger, more elongated, and with denser cristae at the temporal RPE from control eyes. Exclusively at the temporal RPE, SCGx severely affected mitochondrial morphology and dynamics, together with the levels of phosphorylated AMPK (p-AMPK). AMPK activation with metformin restored RPE p-AMPK levels, and mitochondrial dynamics, structure, and function at 4 weeks post-SCGx, as well as visual function and RPE/outer retina structure at 10 weeks post-SCGx. These results demonstrate a key role of the temporal RPE mitochondrial homeostasis as an early target for NE-AMD-induced damage, and that pharmacological AMPK activation could preserve mitochondrial morphology, dynamics, and function, and, consequently, avoid the functional and structural damage induced by NE-AMD. [Display omitted] • Mitochondrial mass is higher at the temporal retinal pigment epithelium (tRPE). • Mitochondria network (MT) at the tRPE is more cohesive and functional. • Superior cervical ganglionectomy (SCGx) affects MT and function at the tRPE. • SCGx induces a decrease in AMP-dependent kinase (AMPK) activation at the tRPE. • AMPK pharmacological activation prevents mitochondrial and SCGx-induced damage. [ABSTRACT FROM AUTHOR]

• Megamitochondria have an unusually cristae structure with a pale matrix and a large volume. • Depending on the level of stress, megamitochondria might have advantages and disadvantages. • Defective mitophagy and an imbalance in mitochondrial dynamics favor the formation of megamitochondria. 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. [ABSTRACT FROM AUTHOR]

• Transplantation of astrocyte-derived mitochondria can improve cell viability, mitochondrial function and suppress apoptosis and inflammation in SI-damaged astrocytes. • Exogenous mitochondria isolated from untreated astrocytes can be incorporated into injured astrocytes and fuse with their mitochondrial networks. • The IKK/NF–κB and AMPK/PGC1α pathways in astrocytes may be involved in the anti-inflammatory effect and restoration of mitochondrial dysfunction mediated by mitochondrial transplantation. • The recovery of neuronal function caused by enhanced astrocytic support via astrocyte–neuron interactions might be a mechanism by which mitochondrial transplantation mitigates TBI-induced secondary injury. Traumatic brain injury (TBI) is a global public-health problem. Astrocytes, and their mitochondria, are important factors in the pathogenesis of TBI-induced secondary injury. Mitochondria extracted from healthy tissues and then transplanted have shown promise in models of a variety of diseases. However, the effect on recipient astrocytes is unclear. Here, we isolated primary astrocytes from newborn C57BL/6 mice, one portion of which was used to isolate mitochondria, and another was subjected to stretch injury (SI) followed by transplantation of the isolated mitochondria. After incubation for 12 h, cell viability, mitochondrial dysfunction, calcium overload, redox stress, inflammatory response, and apoptosis were improved. Live-cell imaging showed that the transplanted mitochondria were incorporated into injured astrocytes and fused with their mitochondrial networks, which was in accordance with the changes in the expression levels of markers of mitochondrial dynamics. The astrocytic IKK/NF–κB pathway was decelerated whereas the AMPK/PGC-1α pathway was accelerated by transplantation. Together, these results indicate that exogenous mitochondria from untreated astrocytes can be incorporated into injured astrocytes and fuse with their mitochondrial networks, improving cell viability by ameliorating mitochondrial dysfunction, redox stress, calcium overload, and inflammation. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME), where immunosuppressive cells such as tumor-associated macrophages (TAMs) proliferate, is the main cause of resistance to antineoplastic treatment for KRAS -driven lung cancer. In this study, we synthesized polymer-based nanoparticles composed of a 16 nm-sized Au core and the amphiphile, poly-(styrene-alt-maleic acid) (PSMA), via a hydrothermal procedure for carrying the multi-receptor tyrosine kinase inhibitor, sitravatinib (Sit), in a new nanodrug (Au@PSMA-Sit). Au@PSMA-Sit was water soluble and showed high sitravatinib loading and good stability under numerous solution conditions, and was degraded by intracellular esterase to release sitravatinib. In Lewis lung carcinoma (LLC) orthotopic tumor mice, Au@PSMA-Sit enhanced antitumor efficiency by remodeling the TME. Immune profiling with single-cell RNA sequencing showed that Au@PSMA-Sit treatment increased the CD8 T cell cluster and decreased the M2-type macrophage cluster compared to treatment with pure sitravatinib. Au@PSMA-Sit reduced LLC cell proliferation and upgraded M1 polarization of LLC-cocultured TAMs through inhibition of TAM receptors (Tyro3, AXL, and MerTK) after intracellular release of sitravatinib. Au@PSMA-Sit promoted endocytosis-induced endoplasmic reticulum (ER) stress-mediated spleen tyrosine kinase signaling activation, which regulated immunosuppressive TAMs metabolism via enhancement of mitochondrial fission and glycolysis leading to immunogenic modulation. Furthermore, Au@PSMA-Sit enhanced immunogenic cell death through endocytosis/ER stress-mediated release of CRT and HMGB1 from LLC cells, leading to dendritic cell maturation and cytotoxic T cell activation. Therefore, macrophage and CD8 T cell depletion using blocking antibodies diminished the antitumor efficiency of Au@PSMA-Sit. Our results indicate the potential of nano-formulated sitravatinib for strengthening anti-cancer effects in the absence of immunotherapy via immunogenic remodeling of the KRAS -mutant lung TME. [Display omitted] • Polymer-based nanoparticle formulation substantially enhances the anti-tumor efficiency of Sitravatinib in lung cancer. • Au@PSMA-Sit simultaneously regulates cancer cells and tumor-associated macrophages via endocytosis-induced ER stress. • Au@PSMA-Sit promotes mitochondrial fusion and glycolysis for M1 polarization in macrophages and induces ICD in cancer cells. [ABSTRACT FROM AUTHOR]

Abstract Aim Endurance exercise (EE) has been reported to confer neuroprotection against Parkinson's disease (PD); however, underlying molecular mechanisms of the protection remain still unclear. Since mitochondrial impairment is commonly observed in the brain of PD patients and animals, this study investigated whether EE-induced neuroprotection is associated with mitochondrial phenotypes, using a mouse model of PD induced by intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Main methods SH-SY5Y cells were cultured with a neurotoxin MPP+ known to cause PD-like symptoms to examine if modifications of mitochondrial morphology are linked to etiology of PD. For in vivo experiments, C57BL/6 male mice were randomly assigned to four groups: control (CON, n = 12), endurance exercise (EXE, n = 12), MPTP (MPTP, n = 12) and MPTP plus endurance exercise (MPTP + EXE, n = 12). Mice assigned to endurance exercise performed treadmill running at 12 m/min for 60 min/day, 5 days/week for 6 weeks. Key findings SH-SY5Y cells exposed to a neurotoxin MPP+ exhibited mitochondrial fragmentation and diminished mitochondrial proteins, and cell death. Similarly, animals administered with MPTP displayed comparable impairments in the substantia nigra pars compacta (SNpc). In contrast, EE intervention restored motor function to control levels and reduced apoptosis. These propitious effects of EE were associated with mitochondrial phenotypic changes such as upregulated anti-apoptotic proteins (e.g., MCL-1 and BLC-2), reduced a pro-apoptotic protein (e.g., AIF), and improved mitochondrial biogenesis and fusion. Significance Our finding that EE-induced mitochondrial phenotypic changes that resist mitochondrial impairment and cell death against PD introduce potential insight into mitochondria as a new therapeutic target for PD. [ABSTRACT FROM AUTHOR]

Mitochondria-endoplasmic/sarcoplasmic reticulum (ER/SR) interaction and mitochondrial fusion/fission are critical processes that influence substrate oxidation. This narrative review summarizes the evidence on the effects of substrate availability on mitochondrial-SR interaction and mitochondria fusion/fission dynamics to modulate substrate oxidation in human skeletal muscle. Evidence shows that an increase in mitochondria-SR interaction and mitochondrial fusion are associated with elevated fatty acid oxidation. In contrast, a decrease in mitochondria-SR interaction and an increase in mitochondrial fission are associated with an elevated glycolytic activity. Based on the evidence reviewed, we postulate two hypotheses for the link between mitochondrial dynamics and insulin resistance in human skeletal muscle. First, glucose and fatty acid availability modifies mitochondria-SR interaction and mitochondrial fusion/fission to help the cell to adapt substrate oxidation appropriately. Individuals with an impaired response to these substrate challenges will accumulate lipid species and develop insulin resistance in skeletal muscle. Second, a chronically elevated substrate availability (e.g. overfeeding) increases mitochondrial production of reactive oxygen species and induced mitochondrial fission. This decreases fatty acid oxidation, thus leading to the accumulation of lipid species and insulin resistance in skeletal muscle. Altogether, we propose mitochondrial dynamics as a potential target for disturbances associated with low fatty acid oxidation. [Display omitted] • Changes in the substrate availability modify mitochondria-SR interaction. • Changes in substrate availability modify mitochondrial fusion/fission. • An appropriate interplay between substrate availability, mitochondrial dynamics, and substrate oxidation prevents the accumulation of lipid species in skeletal muscle [ABSTRACT FROM AUTHOR]

Excessive mitochondrial fission is associated with the pathogenesis of neurodegenerative diseases. Dynamin-related protein 1 (Drp1) possesses specific fission activity in the mitochondria and peroxisomes. Various post-translational modifications of Drp1 are known to modulate complex mitochondrial dynamics. However, the post-transcriptional regulation of Drp1 remains poorly understood. Here, we show that the heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) regulates Drp1 expression at the post-transcriptional level. hnRNP A1 directly interacts with Drp1 mRNA at its 3′UTR region, and enhances translation potential without affecting mRNA stability. Down-regulation of hnRNP A1 induces mitochondrial elongation by reducing Drp1 expression. Moreover, depletion of hnRNP A1 suppresses 3-NP-mediated mitochondrial fission and dysfunction. In contrast, over-expression of hnRNP A1 promotes mitochondrial fragmentation by increasing Drp1 expression. Additionally, hnRNP A1 significantly exacerbates 3-NP-induced mitochondrial dysfunction and cell death in neuroblastoma cells. Interestingly, treatment with 3-NP induces subcellular translocation of hnRNP A1 from the nucleus to the cytoplasm, which accelerates the increase in Drp1 expression in hnRNP A1 over-expressing cells. Collectively, our findings suggest that hnRNP A1 controls mitochondrial dynamics by post-transcriptional regulation of Drp1. [ABSTRACT FROM AUTHOR]

Abstract: In Parkinson's disease mitochondrial dysfunction can lead to a deficient ATP supply to microtubule protein motors leading to mitochondrial axonal transport disruption. Compromised axonal transport will then lead to a disorganized distribution of mitochondria and other organelles in the cell, as well as, the accumulation of aggregated proteins like alpha-synuclein. Moreover, axonal transport disruption can trigger synaptic accumulation of autophagosomes packed with damaged mitochondria and protein aggregates promoting synaptic failure. We previously observed that neuronal-like cells with an inherent mitochondrial impairment derived from PD patients contain a disorganized microtubule network, as well as, alpha-synuclein oligomer accumulation. In this work we provide new evidence that an agent that promotes microtubule network assembly, NAP (davunetide), improves microtubule-dependent traffic, restores the autophagic flux and potentiates autophagosome–lysosome fusion leading to autophagic vacuole clearance in Parkinson's disease cells. Moreover, NAP is capable of efficiently reducing alpha-synuclein oligomer content and its sequestration by the mitochondria. Most interestingly, NAP decreases mitochondrial ubiquitination levels, as well as, increases mitochondrial membrane potential indicating a rescue in mitochondrial function. Overall, we demonstrate that by improving microtubule-mediated traffic, we can avoid mitochondrial-induced damage and thus recover cell homeostasis. These results prove that NAP may be a promising therapeutic lead candidate for neurodegenerative diseases that involve axonal transport failure and mitochondrial impairment as hallmarks, like Parkinson's disease and related disorders. [Copyright &y& Elsevier]

Abstract: Mitochondria move along cytoskeletal tracks, fuse and divide. These dynamic features have been shown to be critical for several mitochondrial functions in cell viability and cell death. After a rapid recall of the proteic machineries that are known to be involved, the review will focus on lipids, other key molecular actors of membrane dynamics. A summary of the current knowledge on lipids and their implication in various cellular membrane fusion/fission processes will be first presented. The review will then report what has been discovered or can be expected on the role of the different families of lipids in mitochondrial membrane fusion and fission processes. [Copyright &y& Elsevier]

Sarcopenia, the age-associated-fragility with loss of skeletal muscle mass and function, often coexists with type 2 diabetes (T2D) in older individuals. Derangement of muscle metabolism and mitochondrial dynamics is critical, particularly in high-energy-demand organs in patients with metabolic disorder. However, targeted therapies to halt or reverse the pathological progression of sarcopenia coexisting with T2D are unavailable. Studies have identified the pathological roles of class I histone deacetylases (HDACs) in both T2D and sarcopenia. In addition to their proinflammatory properties, HDACs are known to modify muscle metabolism and mitochondrial dynamics in both the development of sarcopenia and pathogenesis of diabetes. Proper quality control of mitochondrial dynamics through protein degradation and the synthesis of new proteins may improve skeletal muscle function in sarcopenia. Class I HDAC inhibitors improve energy metabolism and modulate autophagy-related genes in skeletal muscle. However, class IIa HDAC4 plays a protective role in preserving skeletal muscle structure following long-term denervation, and selective inhibition of class IIa HDAC activity had no impact on oxidative metabolism of muscle mitochondria. These findings suggest the vital role of class I HDAC modulation in bioenergetics and mitochondria quality control, and may lead to a novel therapeutic strategy targeting sarcopenia that coexists with T2D. HDAC inhibitors have been approved for clinical applications, and interventions targeting on HDACs may be promising for the treatment of sarcopenia. [ABSTRACT FROM AUTHOR]

• MTX and DOX in clinically relevant doses cause heart mitochondrial injury. • MTX causes more pronounced mitochondrial cardiac proteomic changes than DOX. • Neither MTX- nor DOX-induced proteomic changes resemble cardiac aging. Current cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX's cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18–20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics. Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit α (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype. [ABSTRACT FROM AUTHOR]