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Emerging evidence shows that mitochondria fusion/fission imbalance is related to the occurrence of hyperglycemia-induced vascular injury. To study the temporal dynamics of mitochondrial fusion and fission, we observed the alteration of mitochondrial fusion/fission proteins in a set of different high-glucose exposure durations, especially in the early stage of hyperglycemia. The in vitro results show that persistent cellular apoptosis and endothelial dysfunction can be induced rapidly within 12 hours’ high-glucose pre-incubation. Our results show that mitochondria maintain normal morphology and function within 4 hours’ high-glucose pre-incubation; with the extended high-glucose exposure, there is a transition to progressive fragmentation; once severe mitochondria fusion/fission imbalance occurs, persistent cellular apoptosis will develop. In vitro and in vivo results consistently suggest that mitochondrial fusion/fission homeostasis alterations trigger high-glucose-induced vascular injury. As the guardian of mitochondria, AMPK is suppressed in response to hyperglycemia, resulting in imbalanced mitochondrial fusion/fission, which can be reversed by AMPK stimulation. Our results suggest that mitochondrial fusion/fission’s staged homeostasis may be a predictive factor of diabetic cardiovascular complications.

The Connexin43 gap junction gene GJA1 has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection. Here, using human cells and mice, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 s of GJA1-20k recruitment of actin. Interestingly, GJA1-20k mediated fission is independent of canonical Dynamin-Related Protein 1 (DRP1). We find that GJA1-20k-induced smaller mitochondria have decreased reactive oxygen species (ROS) generation and, in hearts, provide potent protection against ischemia-reperfusion injury. The results indicate that stress responsive internally translated GJA1-20k stabilizes polymerized actin filaments to stimulate non-canonical mitochondrial fission which limits ischemic-reperfusion induced myocardial infarction.

Nicotine contained in traditional cigarettes, hookahs, and e-cigarettes is an important risk factor for cardiovascular disease. Our previous study showed that macroautophagic flux impairment occurred under nicotine stimulation. However, whether nicotine influences mitochondrial dynamics in neonatal rat ventricular myocytes (NRVMs) is unclear. The purpose of this study was to explore the effects and potential mechanism of nicotine on mitophagy, mitochondrial dynamics, apoptosis, and the relationship between these processes in NRVMs. Our results showed that nicotine exposure increased mitochondria-derived superoxide production, decreased mitochondrial membrane potential, and impaired PINK1/Parkin-mediated mitophagic flux in NRVMs. Interestingly, nicotine significantly promoted dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and suppressed mitofusin (MFN)-mediated fusion, which was also observed in the bafilomycin A1-treated group. These results suggest that mitophagic flux impairment may contribute to Drp-1-mediated mitochondrial fission. Finally, nicotine caused excessive mitochondrial fission and contributed to apoptosis, which could be alleviated by mdivi-1, an inhibitor of Drp1. In addition to CTSB, as we previously reported, the enzyme activity of cathepsin L (CTSL) was also decreased in lysosomes after stimulation with nicotine, which may be the main cause of the hindered mitophagic flux induced by nicotine in NRVMs. Pretreatment with Torin 1, which is an inhibitor of mTOR, activated CTSL and ameliorated nicotine-induced mTOR activation and mitophagy impairment, decreased mitochondria-derived superoxide production, and blunted mitochondrial fission and apoptosis. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) or inhibitors of p38 and JNK, which could also alleviate mitophagy impairment, exhibited similar effects as Torin1 on mitochondria. Taken together, our study demonstrated that nicotine treatment may lead to an increase in Drp1-mediated mitochondrial fission by blocking mitophagic flux by weakening the enzyme activity of CTSL and activating the ROS/p38/JNK signaling pathway. Excessive mitochondrial fission induced by nicotine ultimately leads to apoptosis. Torin1 restored the decreased CTSL enzyme activity by removing excessive ROS and alleviated the effects of nicotine on mitophagic flux, mitochondrial dynamics, and apoptosis. These results may provide new evidence on the relationship between mitophagic flux and mitochondrial dynamics and new perspectives on nicotine’s effects on mitochondrial dynamics in cardiomyocytes.

The frequent detection of (2,3-dibromopropyl) phosphate (TDBPP) in environment has led to a consistent risk to organisms. However, little is known about the toxicity of TDBPP exclusive for its carcinogen. Mitochondrion that tightly relates to adverse outcomes once deteriorated is referred as a target of environmental pollutants. Here, we investigated the role of mitochondrial abnormality in development of cellular pathobiology especially lipid deposition when response to TDBPP in mitochondria-rich hepatocyte (AML12) at the same order of magnitude as the environmental concentrations (10-6 mol/L or below) via multiplexed quantitative high content analytic system. The present study claimed TDBPP shifted mitochondria from fusion morphology to fission phenotype charactering by less mitochondrial networks, larger mitochondrial areas and shorter branch length at 10-7 mol/L or above. This dynamic imbalance was triggered by high levels of fis and drp1 genes when treated with TDBPP. The deformation caused by TDBPP reciprocally influenced biogenesis through PGC1α and electron transport chains via ectopic expression of genes encoding for mitochondria complex I and III subunits. Accordingly, we observed high mitoROS level and low mitochondria membrane potential. Consequently, cells contained those abnormal mitochondria were predisposed to accumulating lipids after exposure to TDBPP. Here we showed that TDBPP deteriorated mitochondrial morphology and function, which may induce lipid generation. As for a banned while still emerged contaminant, our study also claimed further exploration on the non-carcinogenic toxicity of TDBPP.

White matter lesions (WMLs) are a type of cerebrovascular disorder accompanied by demyelination and cognitive decline. Dl-3-n-butylphthalide (D1-NBP) is a neuroprotective drug used for the treatment of ischemic cerebrovascular diseases, although the function of DI-NBP on WML is still not clear. This study aims to investigate whether DI-NBP affects cognitive function and ameliorates demyelination in a model of WML. The bilateral carotid artery stenosis (BCAS) mouse model and in vitro brain slice cultures with low glucose and low oxygen (LGLO) treatment were adopted. The Dl-NBP was administered intragastrically for 28 days after BCAS or added at a dose of 50 μm for 48 h after LGLO. Spatial learning and memory were evaluated by an eight-arm radial maze. Demyelination was detected using a TEM. Mitochondrial dynamics were assessed by time-lapse imaging in the cultured brain slices. The function of the synapse was evaluated by the patch clamp technique. In BCAS mice, obvious demyelination and cognitive decline were observed, while both were significantly relieved by a high-dose D1-NBP treatment (100 mg/kg). Along with demyelination, mitochondrial accumulation in the axons was significantly increased in the BCAS mice model, but with the treatment of a high-dose D1-NBP, mitochondrial accumulation was mitigated, and the anterograde/retrograde transport of mitochondria was increased. Following the improved anterograde/retrograde transport of mitochondria, the synapse activity was significantly upregulated while the reactive oxygen species (ROS) generation was remarkably decreased in the cultured brain slices. In addition, we identified syntaphilin (SNPH) as the downstream target of D1-NBP. The overexpression of SNPH mediated the effects of D1-NBP in mitigating axonal mitochondrial accumulation. In conclusion, the D1-NBP treatment significantly relieved demyelination and improved spatial learning and memory in the WML model by promoting mitochondrial dynamics. These neuroprotective effects of D1-NBP were mediated by inhibiting the mitochondrial arching protein, SNPH, which provided a potential therapeutic target for WML.

Glutamate neurotoxicity has been implicated in the initiation and progression of various neurological and neurodegenerative disorders. Therefore, it is necessary to develop therapeutics for the treatment of patients with these devastating diseases. Mitochondrial fission plays an import role in the mediation of cell death and survival. The objective of the present study was to determine whether B355252, a phenoxythiophene sulfonamide derivative, reduces glutamate-induced cell death by inhibiting mitochondrial fission and the nuclear translocation of apoptosis-inducing factor (AIF) in glutamate-challenged HT22 neuronal cells. The results revealed that glutamate treatment led to large increases in the mitochondrial levels of the major fission proteins dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1), but only small elevations in the fusion proteins mitofusin 1 and 2 (Mfn1/2) and optic atrophy 1 (Opa1). In addition, glutamate toxicity disrupted mitochondrial reticular networks and increased the translocation of AIF to the nucleus. Pretreatment with B35525 reduced glutamate-induced cell death and prevented the increases in the protein levels of Drp1, Fis1, Mfn1/2 and Opa1 in the mitochondrial fraction. More importantly, the architecture of the mitochondria was protected and nuclear translocation of AIF was completely inhibited by B35525. These findings suggest that the regulation of mitochondrial dynamics is central to the neuroprotective properties of B355252, and presents an attractive opportunity for potential development as a therapy for neurodegenerative disorders associated with mitochondria dysfunction.

Simple Summary Mitochondria are well known for being the powerhouses of the cell—whether the cell is normal or cancerous. Moreover, they can move, split, fuse themselves, or be eliminated via mitophagy with the help of the interplay between motor proteins and the cell scaffold—especially microtubules. The relationship between mitochondria, microtubules, and motor proteins is altered in cancer, and targeting this molecular machinery can offer a novel weapon in its treatment. In this paper, we review and summarize the state of the art of this approach. Abstract Mitochondria constitute an ever-reorganizing dynamic network that plays a key role in several fundamental cellular functions, including the regulation of metabolism, energy production, calcium homeostasis, production of reactive oxygen species, and programmed cell death. Each of these activities can be found to be impaired in cancer cells. It has been reported that mitochondrial dynamics are actively involved in both tumorigenesis and metabolic plasticity, allowing cancer cells to adapt to unfavorable environmental conditions and, thus, contributing to tumor progression. The mitochondrial dynamics include fusion, fragmentation, intracellular trafficking responsible for redistributing the organelle within the cell, biogenesis, and mitophagy. Although the mitochondrial dynamics are driven by the cytoskeleton—particularly by the microtubules and the microtubule-associated motor proteins dynein and kinesin—the molecular mechanisms regulating these complex processes are not yet fully understood. More recently, an exchange of mitochondria between stromal and cancer cells has also been described. The advantage of mitochondrial transfer in tumor cells results in benefits to cell survival, proliferation, and spreading. Therefore, understanding the molecular mechanisms that regulate mitochondrial trafficking can potentially be important for identifying new molecular targets in cancer therapy to interfere specifically with tumor dissemination processes.

Mitochondria coordinated a lot of vital cellular processes of energy production and distribution. Change of mitochondrial functions has been implicated in cancer progression. The present study aims to investigate the involvement of mitochondria dynamics in LASS2 induced invasion and chemoresistance of bladder cancer cells. J82 and BIU87 cell lines were used for LASS2 plasmid transfection while siRNA knockdown was carried out in 5637 cell line. Matrigel invasion assay and Annexin V/PI staining demonstrated that LASS2 negatively regulated cancer cell invasion and chemoresistance. JC-1 staining suggested that LASS2 overexpression downregulated mitochondrial membrane potential. Mitotracker staining showed that LASS2 induced mitochondrial fusion and inhibited mitochondrial fission. In addition, LASS2 overexpression downregulated expression of mitochondrial fission protein p-Drp1 Drp1 and Fis1. While depletion of LASS2 exhibited the opposite effects. Drp1 inhibitor Mdivi abolished invasion and chemoresistance induced by LASS2 siRNA. Furthermore, we found that LASS2 overexpression could inhibit phosphorylation of ERK, which act upstream of Drp1. ERK inhibitor PD98059 suppressed Drp1 phosphorylation and abrogated the effects of LASS2 depletion. In conclusion, the present study demonstrated that LASS2 inhibits bladder cancer invasion and chemoresistance through regulation of ERK-Drp1 induced mitochondrial dynamics.

Mitochondria play pivotal roles in the ATP production, apoptosis and generation of reactive oxygen species. Although dynamic regulation of mitochondria morphology is a critical step to maintain cellular homeostasis, the regulatory mechanisms are not yet fully elucidated. In this study, we identified miR-200a-3p as a novel regulator of mitochondrial dynamics by targeting mitochondrial fission factor (MFF). We demonstrated that the ectopic expression of miR-200a-3p enhanced mitochondrial elongation, mitochondrial ATP synthesis, mitochondrial membrane potential and oxygen consumption rate. These results indicate that miR-200a-3p positively regulates mitochondrial elongation by downregulating MFF expression. [BMB Reports 2017; 50(4): 214-219].

Orderly mitochondrial life cycle, plays a key role in the pathology of neurodegenerative diseases. Mitochondria are ubiquitous in neurons as they respond to an ever-changing demand for energy supply. Mitochondria constantly change in shape and location, feature of their dynamic nature, which facilitates a quality control mechanism. Biological studies in mitochondria dynamics are unveiling the mechanisms of fission and fusion, which essentially arrange morphology and motility of these organelles. Control of mitochondrial network homeostasis is a critical factor for the proper function of neurons. Disease-related genes have been reported to be implicated in mitochondrial dysfunction. Increasing evidence implicate mitochondrial perturbation in neuronal diseases, such as AD, PD, HD, and ALS. The intricacy involved in neurodegenerative diseases and the dynamic nature of mitochondria point to the idea that, despite progress toward detecting the biology underlying mitochondrial disorders, its link to these diseases is difficult to be identified in the laboratory. Considering the need to model signaling pathways, both in spatial and temporal level, there is a challenge to use a multiscale modeling framework, which is essential for understanding the dynamics of a complex biological system. The use of computational models in order to represent both a qualitative and a quantitative structure of mitochondrial homeostasis, allows to perform simulation experiments so as to monitor the conformational changes, as well as the intersection of form and function.

// Xingchun Gao 1, 2, * , Yajing Mi 1, * , Na Guo 1, * , Zhifang Hu 1 , Fengrui Hu 1 , Dou liu 1 , Lei Gao 1 , Xingchun Gou 1 , Weilin Jin 1, 2, 3 1 Institute of Basic Medical Sciences and Shaanxi key Laboratory of ischemic Cardiovascular Disease, Xi’an Medical University, Xi’an 710021, P. R. China 2 Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China 3 National Centers for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China * These authors contributed equally to this work Correspondence to: Xingchun Gou, email: gouxingchun@189.cn Weilin Jin, email: weilinjin@yahoo.com , weilinjin@sjtu.edu.cn Keywords: glioblastoma, DISC1, mitochondria dynamics, self-renewal, Drp1 Received: August 15, 2016 Accepted: November 07, 2016 Published: November 11, 2016 ABSTRACT Glioblastoma(GBM) is one of the most common and aggressive malignant primary tumors of the central nervous system and mitochondria have been proposed to participate in GBM tumorigenesis. Previous studies have identified a potential role of Disrupted in Schizophrenia 1 (DISC1), a multi-compartmentalized protein, in mitochondria. But whether DISC1 could regulate GBM tumorigenesis via mitochondria is still unknown. We determined the expression level of DISC1 by both bioinformatics analysis and tissue analysis, and found that DISC1 was highly expressed in GBM. Knocking down of DISC1 by shRNA in GBM cells significantly inhibited cell proliferation both in vitro and in vivo . In addition, down-regulation of DISC1 decreased cell migration and invasion of GBM and self renewal capacity of glioblastoma stem-like cells. Furthermore, multiple independent rings or spheres could be observed in mitochondria in GBM depleted of DISC1, while normal filamentous morphology was observed in control cells, demonstrating that DISC1 affected the mitochondrial dynamic. Dynamin-related protein 1 (Drp1) was reported to contribute to mitochondrial dynamic regulation and influence glioma cells proliferation and invasion by RHOA/ ROCK1 pathway. Our data showed a significant decrease of Drp1 both in mRNA and protein level in GBM lack of DISC1, indicating that DISC1 maybe affect the mitochondrial dynamic by regulating Drp1. Taken together, our findings reveal that DISC1 affects glioblastoma cell development via mitochondria dynamics partly by down regulation of Drp1.

Circadian rhythms provide a selective advantage by anticipating organismal nutrient needs and guaranteeing optimal metabolic capacity during active hours. Impairment of circadian rhythms is associated with increased risk of type 2 diabetes and emerging evidence suggests that metabolic diseases are linked to perturbed clock machinery. The circadian clock regulates many transcriptional–translational processes influencing whole cell metabolism and particularly mitochondrial activity. In this review, we survey the current literature related to cross-talks between mitochondria and the circadian clock and unravel putative molecular links. Understanding the mechanisms that link metabolism and circadian responses to transcriptional modifications will provide valuable insights toward innovative therapeutic strategies to combat the development of metabolic disease.

Background Maternal overnutrition including pre-pregnancy, pregnancy and lactation promotes a lipotoxic insult leading to metabolic dysfunction in offspring. Diet-induced obesity models (DIO) show that changes in hypothalamic mitochondria fusion and fission dynamics modulate metabolic dysfunction. Using three selective diet formula including a High fat diet (HFD), Cafeteria (CAF) and High Sugar Diet (HSD), we hypothesized that maternal diets exposure program leads to selective changes in hypothalamic mitochondria fusion and fission dynamics in male offspring leading to metabolic dysfunction which is exacerbated by a second exposure after weaning. Methods We exposed female Wistar rats to nutritional programming including Chow, HFD, CAF, or HSD for 9 weeks (pre-mating, mating, pregnancy and lactation) or to the same diets to offspring after weaning. We determined body weight, food intake and metabolic parameters in the offspring from 21 to 60 days old. Hypothalamus was dissected at 60 days old to determine mitochondria-ER interaction markers by mRNA expression and western blot and morphology by transmission electron microscopy (TEM). Mitochondrial-ER function was analyzed by confocal microscopy using hypothalamic cell line mHypoA-CLU192. Results Maternal programming by HFD and CAF leads to failure in glucose, leptin and insulin sensitivity and fat accumulation. Additionally, HFD and CAF programming promote mitochondrial fusion by increasing the expression of MFN2 and decreasing DRP1, respectively. Further, TEM analysis confirms that CAF exposure after programing leads to an increase in mitochondria fusion and enhanced mitochondrial-ER interaction, which partially correlates with metabolic dysfunction and fat accumulation in the HFD and CAF groups. Finally, we identified that lipotoxic palmitic acid stimulus in hypothalamic cells increases Ca2+ overload into mitochondria matrix leading to mitochondrial dysfunction. Conclusions We concluded that maternal programming by HFD induces hypothalamic mitochondria fusion, metabolic dysfunction and fat accumulation in male offspring, which is exacerbated by HFD or CAF exposure after weaning, potentially due to mitochondria calcium overflux.

Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is observed to cause neuronal death in SCA3 patients. Based on previous studies, proteolytic cleavage of mutant ATXN3 is found to produce truncated C-terminal fragments in SCA3 models. However, whether these truncated mutant fragments disturb mitochondrial functions and result in pathological death is still unclear. Here, we used neuroblastoma cell and transgenic mouse models to examine the effects of truncated mutant ATXN3 on mitochondria functions. In different models, we observed truncated mutant ATXN3 accelerated the formation of aggregates, which translocated into the nucleus to form intranuclear aggregates. In addition, truncated mutant ATXN3 caused more mitochondrial fission, and decreased the expression of mitochondrial fusion markers, including Mfn-1 and Mfn-2. Furthermore, truncated mutant ATXN3 decreased the mitochondrial membrane potential, increased reactive oxygen species and finally increased cell death rate. In transgenic mouse models, truncated mutant ATXN3 also led to more mitochondrial dysfunction, neurodegeneration and cell death in the cerebellums. This study supports the toxic fragment hypothesis in SCA3, and also provides evidence that truncated mutant ATXN3 is severer than full-length mutant one in vitro and in vivo.

Fullerene (C60) derivatives, a unique class of compounds with potent antioxidant properties, have been reported to exert a wide variety of biological activities including neuroprotective properties. Mitochondrial dynamics are an important constituent of cellular quality control and function, and an imbalance of the dynamics eventually leads to mitochondria disruption and cell dysfunctions. This study aimed to assess the effects of carboxylic acid C60 derivatives (C60–COOH) on mitochondrial dynamics and elucidate its associated mechanisms in lipopolysaccharide (LPS)-stimulated BV-2 microglial cell model. Using a cell-based functional screening system labeled with DsRed2-mito in BV-2 cells, we showed that LPS stimulation led to excessive mitochondrial fission, increased mitochondrial localization of dynamin-related protein 1 (Drp1), both of which were markedly suppressed by C60–COOH pretreatment. LPS-induced mitochondria reactive oxygen species (ROS) generation and collapse of mitochondrial membrane potential (ΔΨm) were also significantly inhibited by C60–COOH. Moreover, we also found that C60–COOH pretreatment resulted in the attenuation of LPS-mediated activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling, as well as the production of pro-inflammatory mediators. Taken together, these findings demonstrated that carboxylic acid C60 derivatives may exert neuroprotective effects through regulating mitochondrial dynamics and functions in microglial cells, thus providing novel insights into the mechanisms of the neuroprotective properties of carboxylic acid C60 derivatives.

// Ting-Fang Che 1 , Ching-Wen Lin 2 , Yi-Ying Wu 5 , Yu-Ju Chen 6 , Chia-Li Han 7 , Yih-leong Chang 8 , Chen-Tu Wu 8 , Tzu-Hung Hsiao 9 , Tse-Ming Hong 5, * , Pan-Chyr Yang 1, 2, 3, 4, * 1 Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan 2 Institute of Biomedical Science, Academia Sinica, Taipei 115, Taiwan 3 NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan 4 Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan 5 Institute of Clinical Medicine, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan 6 Institute of Chemistry, Academia Sinica 115, Taipei, Taiwan 7 Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University 110, Taipei, Taiwan 8 Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan 9 Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan * These authors have contributed equally to this work Correspondence to: Pan-Chyr Yang, e-mail: pcyang@ntu.edu.tw Tse-Ming Hong, e-mail: tmhong@mail.ncku.edu.tw Keywords: cancer metastasis, EGFR, mitochondria dynamics Received: May 19, 2015 Accepted: October 06, 2015 Published: October 19, 2015 ABSTRACT Dysfunction of the mitochondria is well-known for being associated with cancer progression. In the present study, we analyzed the mitochondria proteomics of lung cancer cell lines with different invasion abilities and found that EGFR is highly expressed in the mitochondria of highly invasive non-small-cell lung cancer (NSCLC) cells. EGF induces the mitochondrial translocation of EGFR; further, it leads to mitochondrial fission and redistribution in the lamellipodia, upregulates cellular ATP production, and enhances motility in vitro and in vivo . Moreover, EGFR can regulate mitochondrial dynamics by interacting with Mfn1 and disturbing Mfn1 polymerization. Overexpression of Mfn1 reverses the phenotypes resulting from EGFR mitochondrial translocation. We show that the mitochondrial EGFR expressions are higher in paired samples of the metastatic lymph node as compared with primary lung tumor and are inversely correlated with the overall survival in NSCLC patients. Therefore, our results demonstrate that besides the canonical role of EGFR as a receptor tyrosine, the mitochondrial translocation of EGFR may enhance cancer invasion and metastasis through regulating mitochondria dynamics.

Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Hungtington’ Disease (HD) and amyotrophic lateral sclerosis (ALS). Contrary to replicating mammalian cells with a metabolism essentially glycolitic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs. Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

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., Highlights • hnRNP A1 increases Drp1 expression through the interaction with 3′UTR of Drp1 mRNA. • Down-regulation of hnRNP A1 increases mitochondrial elongation by reducing drp1 expression. • Down-regulation of hnRNPA1 inhibits 3-NP-mediated mitochondrial dysfunction. • Over-expression of hnRNP A1 potentiates 3-NP-mediated mitochondrial dysfunction and cell death. • Treatment of 3-NP promotes translocation of hnRNP A1 to the cytoplasm and enhances Drp1 expression.

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.